Copanlisib In Combination Research Articles

Copanlisib in Combination with Rituximab and Bendamustine for Transplant-Ineligible Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients: Results from the Phase II Multicenter Fil_Copa-Rb Trial from Fondazione Italiana Linfomi (FIL)

Background: 60% of Diffuse large B-cell lymphoma (DLBCL) are cured with R-CHOP. Treatment options for relapsed/refractory (R/R) patients (pts) not eligible to high-dose chemotherapy and autologous stem cell transpntation (ASCT) or CAR-T are limited with short-lasting efficacy. The PI3-K inhibitor copanlisib showed activity in B-cell lymphomas including DLBCL. We reported the results of the phase II single arm multicenter FIL Copa-RB trial which investigated the combination copanlisib plus rituximab and bendamustine (copa-RB) in transplant-ineligible R/R DLBCL. Methods: Patients with R/R DLBCL previously treated with 1-3 prior lines, not eligible to ASCT and CAR-T were enrolled to receive 6 cycles of copa-RB q28 days (induction treatment schedule: copanlisib 60 mg i.v. days 1,8,15. Rituximab 375 mg/m2 i.v. day 1, Bendamustine 90 mg/m2 i.v. days 1,2). Patients with at least stable disease continued with a maintenance phase up to 12 q28 day cycles of Copanlisib (60 mg i.v. days 1,15). The primary end point was 12-month progression free survival (PFS) with an expected improvement from 20% to 35% and a calculated sample size of 81 pts. Results: From 11/2019 to 7/2022, 37 pts were enrolled. Median age was 76 years (68-87), 23 (62%) were at IPI ≥3, 25 (68%) had stage IV, 23 (62%) and 14 (38%) received 1 and 2 prior lines and 35% were refractory to the last treatment. The best overall response rate (ORR) was 51%, with 22% CR. With a median follow-up of 12 months, the 12-mo PFS was 25.2% (95%CI:13.6-38.5%) and median PFS 5.5 months (95%CI:3.7-10.0). The 12-mo overall survival (OS) was 49.4% (95%CI:30.7-65.7%) (fig. 1). Nine patients were alive and in continuous response at time of the data cut-off. 91% of the patients experienced grade > 2 adverse events (AE): neutropenia (58%), infections (28%), gastrointestinal (19%), skin (16%) and thrombocytopenia (13%). SARS-COV-2 infection occurred in 19% with 5 deaths. CMV reactivation occurred in 47%, but without infection. Febrile neutropenia was recorded in 2.8%. AEs led to dose interruptions in 19%. Since the slow recruitment, the unfavorable safety profile and the emerging of potentially more effective new treatment options in this setting of patient, the study was interrupted prematurely by steering committee decision. Conclusions: Copa-RB study was conducted in a difficult-to treat R/R DLBCL cohort (elderly, advanced stage) during COVID pandemic that affected its management. Copa-RB induced a good ORR, but it was short lasting with unfavorable safety profile, so the overall activity was modest and did not support further the development of this combination in this setting of patients. A subset of patients had a long-lasting response. A mutational study is ongoing to identify molecular pathways potentially predictive of response to the combination

Safety, Efficacy and T-Cell Predictive Biomarkers in a Phase I Trial of Copanlisib+Nivolumab in Patients with Richter's Transformation (RT) or Transformed Non-Hodgkin Lymphoma (tNHL)

Background. Despite advances in targeted and cellular therapy, outcomes among patients (pts) with RT and tNHL remain dismal. Copanlisib (COPA) is a selective, small molecule, PI3Kinhibitor which preferentially targets the p110αδ isoforms . COPA has shown clinical efficacy in NHL and is an approved therapy for follicular lymphoma (FL). Nivolumab (NIVO) is a PD-1 antagonist which has demonstrated activity in NHL. Furthermore, combined targeting of PI3K and PD-1 has demonstrated synergy in pre-clinical lymphoma models. Here we report results of a phase 1 study of COPA in combination with NIVO in pts with R/R RT or tNHL (NCT03884998) and correlate response to treatment and T cell functionality in RT. Methods. This ongoing multicenter, open-label, phase I, investigator-sponsored study is enrolling pts with RT or tNHL, age ≥18 years, whose disease has relapsed or was refractory to ≥1 prior line of therapy. The phase I portion of the study follows a standard 3+3 design, followed by a dose expansion of 16 evaluable pts, with two planned dose levels of COPA administered IV (dose level [DL]1 - 45 mg on days 1, 8 and 15 and DL2 - 60 mg on days 1, 8 and 15 of a 28-day cycle). NIVO 240 mg is given IV on days 1 and 15. Pts receive up to 24 cycles of therapy. Dose limiting toxicities (DLT) were defined as grade ≥4 hematologic lasting > 7 days or grade ≥3 non-hematologic toxicities. The primary study objective is to evaluate the maximum tolerated dose (MTD) of the combination; secondary objectives are preliminary efficacy by Lugano criteria. Exploratory objectives include T-cell functionality assessed by flow cytometry analysis of cell subsets as well as scRNA-Seq performed on biospecimens banked from pts pre-treatment, after cycles 1 and 5, and at the end of treatment. Results. The study enrolled 25 pts to date, 11 in dose finding (8 at DL1 and 3 at DL2) and 14 in dose expansion cohorts. Fourteen pts had RT and 11 had tNHL (10 tFL and 1 transformed lymphoplasmacytic lymphoma). Median (med) age was 65 years (32-77), 88% (22/25) had ECOG performance status 0-1. Pts had received a med of 4 prior lines of therapy (range, 1-10); 8 pts (2 RT, 6 tNHL) had CAR T cells. During dose finding, 8 pts were treated at DL1 (45 mg COPA), of which 2 pts did not complete the DLT period due to rapidly progressive disease and were replaced. No DLTs were observed in 6 evaluable pts at DL1. At DL2 (60 mg COPA), three DLTs (neutropenia, thrombocytopenia) occurred in 2 pts determining the MTD of COPA to be 45 mg. After a median follow-up of 14 months (range 1.8-20.6), the most common treatment-related adverse events (AEs, any grade) were diarrhea and anemia (Table 1). Twenty-three pts went off protocol after a med of 3 cycles (range 1-20); 2 remain on treatment. Sixteen pts discontinued therapy due to progressive disease and 6 due to AEs. Among the 23 efficacy-evaluable pts who completed at least one cycle of therapy, 10 pts achieved a response (ORR 43%). Pts with tFL had an ORR of 60% (2 CR and 4 PR) with median progression free survival (mPFS) 4.8 months (95%CI: 0.4-16.8) and median duration of response (mDOR) 10.2 months (95%CI: 2.0-13.6) (Figure 1). Pts with RT had an ORR of 33% (2 CR and 2 PR) with mPFS 2.0 months (95%CI: 0.7-4.9) and mDOR not reached (95%CI: 3.0-NA). Analysis of paired samples from pts using flow cytometry and scRNA-Seq demonstrated an increase in circulating CD8+ T cell population and a decrease in exhaustion markers (PD1, CTLA-4) after exposure to COPA/NIVO. Analysis of 2 responding RT pts by scRNA-Seq demonstrated downregulation of MYC in tumor cells and upregulation of IFN response in T cells. This pattern was not observed 3 RT non-responders (NRs). By contrast, CD8+ effector T-cells from NRs exhibited downmodulation of the IFN response after cycle 1 of treatment and concurrent activation of p53-regulated genes and apoptotic genes. Tregs sourced from RT responders showed enhanced expression of apoptosis pathways after treatment, while these pathways were downregulated in NR Tregs. Discussion. We identified COPA 45 mg IV on days 1, 8 and 15 as the MTD/RP2D in combination with NIVO in pts with R/R RT and tFL. This combination was generally well-tolerated and had activity, particularly in pts with with tFL. We observed key differences in gene expression patterns in T cell subsets between the responders and NRs. Downregulation of MYC in the tumor, activation of the apoptotic program in Tregs and enhanced CD8 T-cell IFN response were associated with treatment response in RT. Accrual is ongoing.

Copanlisib in Combination with Nivolumab in Subjects with Relapsed/Refractory Diffuse Large B-Cell Lymphoma and Primary Mediastinal Large B-Cell Lymphoma: A Phase II Study

Introduction: Diffuse Large B-cell Lymphoma (DLBCL) are aggressive B-cell non-Hodgkin lymphomas (NHL). One particular subtype, Primary Mediastinal B-cell Lymphoma (PMBCL), is often grouped with DLBCL, but it possesses distinct biological and clinical characteristics. While initial therapy successfully cures approximately two-thirds of patients (pts), those who do not respond or experience progression within the first two years have a poor prognosis despite novel cellular therapies and bispecifics and ultimately succumb to their disease. There is a pressing need for more effective therapeutic approaches in this patient population. Recent advances in the understanding of DLBCL pathogenesis have led to the targeting of various signaling pathways, including the PI3K-AKT-mTOR pathway. One such drug, copanlisib (C), a pan-PI3K inhibitor with potent PI3K-α/PI3K-δ inhibition, exhibited activity in both indolent and aggressive NHL. In preclinical studies using a DLBCL mouse model, treatment with C effectively reduced the immunosuppressive tumor-infiltrating T-regulatory cells (Tregs). Moreover, when combined with a surrogate anti-mouse programmed death -1 (PD-1) blocker, C demonstrated significant in vivo responses (75%) compared to the monotherapy groups (0%). These findings support the rationale for exploring the combination of nivolumab, a PD-1 blocker, and copanlisib (C-N) in DLBCL. Thus, a phase 2 prospective study has been developed, focusing on two relapsed/refractory (RR) cohorts (DLBCL and PMBCL), treated with the combination of C-N. A prespecified interim analysis was planned upon enrollment of 14 pts. Herein, we report outcomes of the 12 enrolled pts, as the study was halted prematurely due to a safety signal deemed possibly related to the combination. Study design: C 60 mg was given intravenously on days 1, 8, and 15 during cycles 1-8, and on days 1 and 15 in subsequent cycles. N 240 mg IV was given on days 1 and 15 during cycles 1-8, and 480 mg on day 1 on subsequent cycles. Each treatment cycle is 28 days. Therapy was given for up to 2 years, as long as there is no disease progression or unacceptable side effects. The primary objective of the study is to determine the ORR, which includes complete and partial responses (CR+PR). Secondary objectives include evaluating the safety of the combination, as well as assessing progression-free survival (PFS), duration of response (DOR), CR, and overall survival (OS). The study plan was to enroll a maximum of 106 pts, including a safety cohort of 6 pts. The study received funding from Bayer and conducted through NCI-CTEP (NCI Protocol #10193; NCT03484819). Results: Twelve pts who received at least one cycle of C-N were included in this analysis. Pt characteristics are illustrated in table 1. All enrolled pts had DLBCL histology. Only one patient received a prior autologous stem cell transplant. Interestingly 4/12 received prior chimeric antigen receptor T-cell therapy (CART). Of the 12 enrolled pts, seven were evaluated for response. The ORR was 25% (3/12) (95% CI: 5 - 57%), all CR. The median number of cycles received was 2.5 (range 1-24) with two pts receiving 23 and 24 cycles. Observed grade 3 and higher adverse events (AEs) were as follows: non-hematologic AEs in 10/12 (83.3%), while hematologic AEs were seen in 5/12 (41.7%) pts. A relatively higher incidence of cardiac events (4/12) were noted including one cardiac arrest after one cycle of therapy, and four atrial fibrillation events, all grade 3, but only two were deemed possibly attributed to therapy. The cardiac arrest was deemed unrelated to therapy. Conclusions: C-N combination had modest clinical activity in pts with R/R DLBCL with some prolonged responses. However, due to the relatively high number of cardiac events and the changing therapeutic landscape with recent approvals, a decision was made to halt the study. These findings likely reflect possibly older and sicker patient population. Biomarker studies for predictors of response are under consideration.

Copanlisib population pharmacokinetics from phase I-III studies and exposure-response relationships in combination with rituximab.

Copanlisib dose selection was established under the maximum tolerated dose paradigm, and no dedicated dose-finding studies have investigated copanlisib dose selection when used in combination with rituximab. In CHRONOS-3, copanlisib plus rituximab demonstrated significantly improved progression-free survival versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (iNHL). We conducted a comprehensive investigation of copanlisib population pharmacokinetics (PopPK) from a pooled analysis of 712 patients across nine copanlisib phase I-III studies and exposure-response (ER) relationships for efficacy and safety from the 1-year follow-up of CHRONOS-3. PopPK analyses examined the impact of demographic, laboratory, and comedication covariates on copanlisib between-patient PK variability. Individual static and time-varying exposure estimates were derived to investigate exposure-efficacy and exposure-safety relationships. Multivariate Cox proportional hazards and logistic regression analyses examined ER relationships with consideration of predefined potentially prognostic demographic-, laboratory-, and/or disease-related baseline covariates. Copanlisib PK were best described by a three-compartment model with first-order elimination. Individual identified covariates had modest effects on copanlisib PK and were generally in line with known copanlisib disposition properties. In CHRONOS-3, ER analyses showed a significant relationship between time-varying exposure estimates and progression-free survival, and no significant exposure-safety relationships. Thus, lower copanlisib doses may result in reduced efficacy but not necessarily improved safety or tolerability. These outcomes substantiate the current intermittent dosing regimen of copanlisib 60 mg on days 1, 8, and 15 of a 28-day cycle and support the observed clinical results of copanlisib in combination with rituximab in the iNHL population.

Abstract CT082: Next-generation sequencing (NGS) and cytokine assessment from a phase III study of copanlisib in combination with rituximab in patients with indolent non-Hodgkin lymphoma (iNHL) - associations with survival endpoints

Abstract Introduction: The PI3K inhibitor copanlisib (C) plus the anti-CD20 antibody rituximab (R) was superior to R plus placebo (P) in patients (pts) with relapsed iNHL (Matasar et al. Lancet Oncol 2021). We previously reported that C+R improved median progression-free survival (PFS) in the iNHL, follicular lymphoma (FL), and non-FL groups, with a statistically significant improvement in the PTEN-positive population (Shalini et al., AACR 2022). Here we conducted NGS analysis from pts treated with either C+R or P+R for possible impact on PFS outcomes. We also determined if there was an association between plasma cytokine levels at baseline with survival. Methods: Adult pts with relapsed B-cell iNHL were randomly assigned 2:1 to either C+R or P+R; standard dosing on a 28-day cycle applied. Either fresh or archival tumor tissues were collected for central pathology review and biomarker analysis. NGS was conducted using the TSO500 platform for 476 genes. Analyses included EZH2 and BCL2 mutation status in FL subset, and other genes for FL subsets and overall iNHL, as prognostic and predictive markers. The effect of mutations on PFS and overall survival (OS) outcomes was assessed. Cytokines from baseline plasma were assessed using the multiplex MSD platform (71-plex). Association between cytokine levels and PFS and OS were explored. Results: Baseline tumor samples were evaluable by NGS from 200 pts; 127 C+R and 73 P+R. Variant alleles with frequencies >10% were analyzed. One quarter (25.7%) of FL pts were determined to have EZH2 mutations. C+R treatment significantly improved PFS for FL pts with in mutant EZH2 (p=0.0066) compared to P+R. FL pts with mutant BCL2 had a statistically improved PFS compared to WT BCL2 when receiving C+R treatment. Plasma samples were available for 71-plex assessment in 373 pts; 246 C+R and 127 P+R. Pts were assigned as high or low baseline cytokine groups based on the median values. For majority of cytokines, the low cytokine group correlated with better PFS for all pts, FL and Other iNHL pts in the C+R arm. For OS, there were too few events at the time of primary data cutoff to make any associations. However, with longer follow up (2 years from primary completion) there was a significant improvement in OS in iNHL pts with low IL2 values at baseline receiving C+R compared to pts receiving P+R; HR 0.495 (95%CI: 0.270,0.908), p=0.0230. This association was only seen for pts with low (or undetected) levels of IL2 at baseline. Conclusions: Mutation status was associated with improvements in PFS in FL pts with mutant BCL2 or mutant EZH2 treated with C+R. iNHL pts with low plasma levels of IL2 levels treated with C+R showed a significant improvement in OS. Citation Format: Shalini Chaturvedi, Anke Weispfenning, David Bauer, Rong Du, Tine Descamps, Sara Bellinvia, Teresa Lunt, Lidia Mongay Soler, Barrett H. Childs, Pier Luigi Zinzani. Next-generation sequencing (NGS) and cytokine assessment from a phase III study of copanlisib in combination with rituximab in patients with indolent non-Hodgkin lymphoma (iNHL) - associations with survival endpoints [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT082.

Abstract CT158: BrUOG360: A phase Ib/II study of copanlisib combined with rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC)

Abstract Background: Molecular alterations in genes regulating homologous recombination (HR) confer sensitivity of mCRPC to poly ADP-ribose polymerase inhibitors (PARPi). Increased activation of thePI3K-AKT-mTOR pathway in mCRPC contributes to tumor progression and represents an important therapeutic target. Preclinical studies have shown that PI3K inhibitors (PI3Ki) impair HR and sensitize cancer cells to PARPi even in the absence of HR gene mutations. We hypothesize that dual PI3K and PARP inhibition may improve clinical outcomes of mCRPC. We describe preliminary results of a phase Ib/II study investigating safety of the combination of copanlisib (pan-class I PI3Ki) and rucaparib (PARP-1, -2 and -3 inhibitor). Methods: Enrollment criteria included progressive mCRPC, prior androgen inhibitors (abiraterone, enzalutamide, and/or apalutamide); prior taxane chemotherapy was allowed. HR defects (HRD) was not required for the phase Ib but was an inclusion criterion for the Phase II component of the trial. The phase I followed a standard 3+3 escalation design. Dose level (DL) 1 consisted of rucaparib 400 mg PO BID continuously and copanlisib 45 mg IV days 1, 8 and 15 every 28 days; in DL -1 the copanlisib was reduced to 45 mg days 1 and 15 only. Adverse events (AE) were graded by CTCAE v5.0. The primary aim of the phase I was to establish the MTD and the recommended phase II dose (RP2D) of copanlisib in combination with rucaparib. Results: Thirteen patients were enrolled with a median age of 64 (55-78) and a median baseline PSA of 11.7 ng/mL (0.015-1939.2). Nine patients (69%) received prior chemotherapy (docetaxel [6], cabazitaxel [3]). Seven patients had HRD (54%) BRCA1 (1), BRCA2 (4), CDK12 (1), and FANCA (1). Treatment-related AEs included grade 2 (G2) leukopenia (46%), G2/G3 anemia (31%), G2/G3 rash (31%). Two dose-limiting toxicities (DLTs) were observed in 5 patients treated in DL 1: G3 rash and G3 AST/ALT elevation attributed to both drugs. Six patients were treated at DL -1 without DLTs; this was identified as the RP2D. Two additional patients have been treated at this dose in Phase II of the study. By RECIST 1.1 criteria, one patient (8%) achieved a partial response (BRCA1 mutation) and three (23%) achieved stable disease resulting in a clinical benefit rate of 30.7%. Median duration of treatment was 12 weeks. One patient harboring a PALB2 VUS mutation remained on treatment for 21.7 months. Of 13 evaluable patients, there were 2 confirmed PSA responses (15%) (one patient without an HRD and one with a BRCA1 mutation). Conclusions: The combination of rucaparib and copanlisib is well tolerated. The RP2D was rucaparib 400mg BID with copanlisib 45mg (D1, D15; 28-day cycle) with signal of efficacy in patients with and without HRD. Clinical trial information: NCT04253262. Citation Format: Matthew J. Hadfield, Andre De Souza, Dragan Golijanin, Roxanne Wood, Adam Olszewski, Sheldon L. Holder, Wafik S. El-Deiry, Rahul Aggarwal, Anthony Mega, Benedito A. Carneiro. BrUOG360: A phase Ib/II study of copanlisib combined with rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT158.

Abstract 4861: Copanlisib enhances the effectiveness of anti-PD1 therapies for colorectal cancer

Abstract Introduction: Immunotherapies are increasingly being used for patients diagnosed with cancer, however, for metastatic colorectal cancer (CRC), more than 95% of patients have shown little to no clinical benefit to immunotherapy. Previous work from our lab has shown that copanlisib, a PI3K inhibitor, was found to enhance MHC class I expression in Kras mutant CT26 murine colon cancer cells. Here we examine the potential for anti-cancer activity with the combination of copanlisib and anti-PD1 treatments using this model. Methods: The impact of copanlisib on CT26 cells was performed using the WST assay and the expression of MHC class I was assessed using flow cytometry. CT26 flank allografts were generated in Balb/C mice and subsequently treated for 15 days with copanlisib (10 mg/kg), anti-PD1 (0.2 mg, BioXCell) or the combination. An IgG2a antibody (BioXCell) was used as a control. Tumors were measured twice a week using a caliper. Tumors were excised, and prepared for immunohistochemistry for CD8, CD4, perforin, granzyme B, and F480 was performed. Staining was quantified as the number of positive staining cells per 20X field of view (FOV). Results: CT26 viability in response to 200 nM copanlisib was relatively unchanged as compared with untreated controls. Via flow cytometry, a 75% increase in mean fluorescent intensity (MFI) for MHC class I was observed comparing control to copanlisib (p=0.003). In vivo, after 15 days there was no difference in the growth rate of those cancers treated with control versus copanlisib or anti-PD1. A significant reduction in growth rate was observed with the combination of anti-PD1 with copanlisib compared to the other arms (median fold change=3.62; control: 7.49, p=0.002, copanlisib: 8.88, p=0.003; anti-PD1: 8.93, p=0.002). There were no differences in CD8 T cell and perforin expression between the treatment groups. Granzyme B expression was higher in the combination compared (median/FOV= 44) to the control (27, p= 0.01). Additionally, a significant reduction in F480 expression was seen in the combination compared to the other treatment groups (median/FOV=43; control: 139, p<0.001, copanlisib: 110, p<0.001; anti-PD1:149, p<0.001). Conclusions: In conclusion, copanlisib in combination with anti-PD1 demonstrated enhanced anti-tumor activity in Balb/c mice that were injected with CT26 CRC cells. This response was correlated with increased granzyme B expression and a reduction in macrophages with the combination treatment. Further studies will expand on the mechanism of this combination therapy. Citation Format: Alexa E. Schmitz, Kennedy J. Maduscha, Sarbjeet Makkar, Cheri A. Pasch, Rebecca A. DeStefanis, Philip B. Emmerich, Dustin A. Deming. Copanlisib enhances the effectiveness of anti-PD1 therapies for colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4861.

A Phase I Trial of PI3Kαδ Inhibitor Copanlisib in Combination with Nivolumab in Patients with Richter's Transformation (RT) or Transformed Non-Hodgkin Lymphoma (tNHL)

A Phase I Trial of PI3Kαδ Inhibitor Copanlisib in Combination with Nivolumab in Patients with Richter's Transformation (RT) or Transformed Non-Hodgkin Lymphoma (tNHL)

Abstract A32: Copanlisib plus rituximab vs placebo plus rituximab in patients with follicular lymphoma: 1-year follow-up of the Phase III, randomized CHRONOS-3 trial

Abstract Introduction: In the Phase III CHRONOS-3 trial investigating the efficacy and safety of the PI3K inhibitor copanlisib in combination with rituximab (C+R), superior efficacy in progression-free survival (PFS) was demonstrated vs placebo plus rituximab (P+R) in patients (pts) with relapsed indolent non-Hodgkin lymphoma (iNHL; hazard ratio [HR] 0.52), including in the subset with follicular lymphoma (FL; HR 0.58) (data cut-off Aug 31, 2020) (Matasar et al. Lancet Oncol 2021). Here we report an updated 1-year follow-up analysis for the subset of pts with FL (data cut-off Aug 6, 2021).Methods: Eligible pts with relapsed iNHL who were progression- and treatment-free for ≥12 months (mo) after the last R-containing regimen, or for >6 mo if unwilling/unfit to receive chemotherapy, were randomized 2:1 to C+R or P+R. Treatment continued until progression or unacceptable toxicity. C 60 mg flat dose was administered i.v. on days 1, 8, and 15 (28-day cycle) and R 375 mg/m2 i.v. on days 1, 8, 15, and 22 of cycle 1 and on day 1 of cycles 3, 5, 7, and 9. Primary endpoint was centrally assessed PFS. Secondary efficacy endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR), complete response rate (CRR), and treatment-emergent adverse events (TEAEs). As part of biomarker analysis, PTEN expression level was evaluated using immunohistochemistry.Results: The FL subset comprised 275 pts (184 C+R and 91 P+R). C+R reduced the risk of progression or death by 43% vs P+R; median PFS was 23.2 mo (95% confidence interval [CI] 19.2, 33.1) for C+R and 16.6 mo (11.0, 19.6) for P+R (HR 0.57 [95% CI 0.41, 0.80]. ORRs were 85% vs 56% for C+R vs P+R; CRRs were 38% vs 21%. Median DoR was 25.7 mo (17.2, 31.5) for C+R vs 18.2 mo (12.3, 26.3) for P+R (HR 0.75 [95% CI 0.49, 1.14]); for pts achieving a complete response, median DoR was not reached for C+R vs 24.7 mo (10.8, 29.7) for P+R (HR 0.41 [0.19, 0.87]), with DoR rates at 36 months 63% vs 23%. Median OS was not estimable, and no significant benefit was seen for C+R over P+R (HR 0.95 [95% CI 0.52, 1.74]). Hyperglycemia (76%), hypertension (54%), and decreased neutrophil count (38%) were the most common TEAEs in the C+R arm, consistent with the study population. Grade 5 events occurred in 5 pts (3%) in the C+R arm; 1 (1%) was deemed treatment-related. Of 119 pts with FL who were evaluable for PTEN analysis, 41 (34%) were positive. Percent PTEN positivity was not correlated to best overall response (p=0.44) or responsiveness (p=0.08). Median PFS was improved in PTEN-negative pts regardless of treatment. PTEN-positive pts had improved PFS with C+R vs P+R (p=0.005).Conclusion: Pts with FL from the CHRONOS-3 trial continued to show superior efficacy with C+R vs P+R and an acceptable safety profile 1 year after the primary disclosure, supporting the long-term use of C+R in pts with relapsed FL. Exploratory analysis suggests pts with PTEN-positive disease may experience significant benefit with C+R. Citation Format: Marcelo Capra, Fangfang Lv, Wei Li, Tongyu Lin, Eduardo Yañez, Jifeng Feng, Aryan Hamed, Xiaoling Li, Toshiki Uchida, Ming-Chung Wang, Koji Izutsu, Antonio Salar, Katya Sapunarova, Guray Saydam, Jan Zaucha, Lidia Mongay Soler, Shalini Chaturvedi, Anjun Cao, Barrett H Childs, Pier Luigi Zinzani, Matthew J Matasar. Copanlisib plus rituximab vs placebo plus rituximab in patients with follicular lymphoma: 1-year follow-up of the Phase III, randomized CHRONOS-3 trial [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A32.

Abstract LB523: Biomarker assessment of PTEN protein expression and gene expression profiling (GEP) in a phase III study of copanlisib in combination with rituximab in patients with indolent non-Hodgkin lymphoma (iNHL)

Abstract Introduction: The combination of the PI3K inhibitor copanlisib (C) plus the anti-CD20 antibody rituximab (R) has been shown to be superior to R plus placebo (P) in patients with relapsed iNHL (Matasar et al. Lancet Oncol 2021). We report here the biomarker analysis to assess correlation with response of baseline samples for PTEN expression and GEP signatures. Methods: Adult patients with relapsed B-cell iNHL were randomly assigned 2:1 to either C + R or P + R; standard dosing on a 28-day cycle applied. Either fresh or archival tumor tissues were collected for central pathology review and biomarker analysis. Extraction of the formalin-fixed, paraffin-embedded (FFPE) tissue slides was performed using the Qiagen AllPrep DNA/RNA FFPE Kit, where quality was assessed using a combination of Agilent TapeStation for integrity and ThermoFisher NanoDrop for quantity and purity. Immunohistochemistry (IHC) for PTEN expression was performed by Mosaic Laboratories (Lake Forest, CA, USA) and RNA sequencing analysis was performed by Almac Diagnostics (Durham, NC, USA). GEP was also conducted using claraT pathway signatures provided by Almac. Results: Patients with complete, very good partial, and partial objective responses were combined in a “responders” group and compared against all other patients (“non-responders” group). Data from PTEN IHC were available for 222 patients (149 for C + R; 73 for P + R). There was no statistically significant difference in response with PTEN presence or absence for the 3 subgroups - total iNHL, follicular lymphoma (FL), and non-FL. Also, baseline PTEN expression did not show significant correlation with best overall response. C + R treatment improved median progression-free survival (PFS) for all patients, with a statistically significant benefit to those with PTEN presence in all 3 subgroups. For patients treated with P + R, Kaplan-Meier plots and log-rank tests showed statistically improved median PFS in patients with PTEN absence vs PTEN presence in overall iNHL (p=0.031) and FL (p=0.0021). Data from GEP were available for 202 patients (133 for C + R; 69 for P + R). The association with best overall response and PFS was analyzed using specific biomarker gene sets and/or 23 preselected clinical parameters. Association of GEP analysis based on hypothesis-based modeling, single-gene hypothesis-free modeling, and claraT pathway signatures showed no predicted responsiveness or PFS that was statistically significant. Conclusions: C + R improved median PFS in the overall iNHL, FL, and non-FL groups, with a statistically significant improvement in the PTEN-positive population. In the P + R group, PTEN-positive patients had worse PFS in all 3 subgroups. Data from GEP and pathway analysis did not show correlation with overall response or PFS. Citation Format: Shalini Chaturvedi, Anke Schulz, Lidia Mongay Soler, Barrett H. Childs, Matthew Matasar, Pier Luigi Zinzani. Biomarker assessment of PTEN protein expression and gene expression profiling (GEP) in a phase III study of copanlisib in combination with rituximab in patients with indolent non-Hodgkin lymphoma (iNHL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB523.

BrUOG360: A phase Ib/II study of copanlisib combined with rucaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

128 Background: mCRPC with alterations in genes associated with homologous recombination (HR) DNA repair (e.g., BRCA1/2) is sensitive to poly ADP-ribose polymerase inhibitors (PARPi). Preclinical studies showed that PI3K inhibitors (PI3Ki) impairs HR and sensitize cancer cells to PARPi even in the absence of HR gene mutations. These results support our hypothesis that dual PI3K and PARP inhibition may improve clinical outcomes in progressive mCRPC. We describe preliminary results of a phase Ib/II study investigating safety of the combination of copanlisib (pan-class I PI3Ki) and rucaparib (PARP-1, -2 and -3 inhibitor). Methods: Enrollment criteria included progressive mCRPC, prior androgen inhibitors (abiraterone, enzalutamide, and/or apalutamide); prior taxane chemotherapy was allowed. HR-deficiency was not required for the phase Ib. The phase I followed a standard 3+3 escalation design. Dose schema: rucaparib (continuous oral administration twice daily) 400mg (dose level [DL] -1, 1), 500mg (DL 2) or 600mg (DL 3,4) and intravenous copanlisib (45mg D1, D15 (DL -1, -2); 45mg, D1, D8, D15 (DL 1, 2, 3); 60mg, D1, D8, D15 (DL 4); 28-day cycle). Adverse events (AE) were graded by CTCAE v5.0. The primary aim of the phase I was to establish the MTD and the recommended phase II dose (RP2D) of copanlisib in combination with rucaparib. Results: Eleven pts were enrolled with a median age of 63 (55-78) and median PSA of 12 ng/mL (0.018–2,101). Seven pts (63%) received prior chemotherapy (docetaxel [7], cabazitaxel [3]). Pathogenic HR mutations included BRCA1 (1), BRCA2 (3), CDK12 (1), and FANCA (1). Treatment-related AE included grade 2 (G2) leukopenia (30%), G2 anemia (20%), G2 rash (20%). Two dose-limiting toxicities (DLTs) were observed in DL 1: G3 rash and G3 AST/ALT elevation attributed to both drugs. Six pts were treated at DL -1 without DLTs. The RP2D was rucaparib 400mg BID with copanlisib 45mg (D1, D15; 28-day cycle). There were 2 confirmed PSA50 responses among 7 evaluable pts (28%). One pt had BRCA2 loss and 1 had PALB2 VUS (ongoing PSA response for 14 mo). Three stable disease and 1 partial response were observed among 6 pts evaluable by RECIST 1.1. Conclusions: The combination of rucaparib and copanlisib is well tolerated. The RP2D was rucaparib 400mg BID with copanlisib 45mg (D1, D15; 28-day cycle) with signal of efficacy. Enrollment in a phase 2 expansion cohort in HR-mutated mCRPC is ongoing. Clinical trial information: NCT04253262.

Abstract P5-16-08: Phase Ib/II trial evaluating safety and efficacy of copanlisib (PI3K inhibitor) and trastuzumab in pre-treated advanced HER2-positive breast cancer: Results from the PantHER study

Abstract Background: De novo and acquired resistance to HER2 directed therapy is frequently encountered. Upregulation of the phosphatidylinositol-3-kinase (PI3K) pathway is an important mediator of treatment resistance. This can occur through an activating mutation of the PIK3CA gene or PTEN loss. PIK3CA mutations are present in approximately 20% of HER2 positive breast cancers and as such, the PI3K pathway has emerged as an attractive target for restoring sensitivity to HER2 directed therapy. Methods: We performed a single arm, multicentre, open label Phase Ib/II trial. Patients (pts) with advanced HER2-positive breast cancer whose disease had progressed on at least 1 line of Trastuzumab/T-DM1 based treatment in the metastatic setting were eligible if they met following criteria: ECOG PS ≤ 2 and adequate organ function. Pts with treated, controlled brain metastases were permitted to enrol. Exclusion criteria included uncontrolled hypertension or diabetes mellitus. Pts on Phase IB were treated according to a 6+6 study design with a dose escalation schedule of Copanlisib IV (level 1 = 45mg, level 2 = 60mg) on Day 1, 8 and 15 of a 28-day cycle along with a fixed dose of Trastuzumab 2mg/kg weekly. Phase II treatment was the MTD (maximum tolerated dose) of Copanlisib in combination with Trastuzumab. Archival tumour tissue, voluntary biopsies and serial plasma samples were collected for genomic sequencing. Primary endpoints were MTD (Phase I) and clinical benefit rate (CBR) which was defined as complete response (CR) or partial response (PR) at any time point; or stable disease (SD) lasting at least 24 weeks (Phase II). Secondary endpoints included safety and tolerability, tumor response rate, duration of response, time to treatment failure (TTF) and progression free (PFS) and overall survival (OS). Results: Twelve pts were enrolled in Phase IB. No dose limiting toxicity was observed. The MTD was established as Copanlisib 60mg and Trastuzumab 2mg/kg. Fourteen pts were enrolled in Phase II (6 pts treated at the MTD in Phase IB were included in the final Phase II analysis resulting in a total of 20 pts). The median number of lines of prior treatment in the metastatic setting was 3 (1-8). The most common grade 3-4 toxicities encountered in the Phase Ib/II cohorts included hypertension (n=7, 27%), hyperglycaemia (n=2, 8%) and vomiting (n=2, 8%). Three pts discontinued treatment due to toxicity. The median follow-up for the Phase II cohort was 7.5 months (95% CI 6.0-14.5). PR was observed in 4 pts (20%) and SD (at any time point) was seen in 8 pts (40%). The CBR was 30% (n=6). The duration of response was 15.0 weeks (95% CI 4.9 - 16.1). The median TTF was 11.9 weeks (95% CI 7.5 - 21.1). The median PFS was 3.0 mo (95% CI 0.2 - 5.8) and OS was 14.0 mo (95% CI 5.2-22.8). At the time of analysis, 9 of 20 patients were alive. PIK3CA mutations were detectable in the archival tissue of 11 of 26 pts (42%). PIK3CA hotspot mutations (H1047R, E542K and E545K) were detectable in the plasma of all 26 pts at various points throughout treatment. Pre and post treatment biopsies of 2 pts in the Phase IB trial revealed somatic mutations in DNAH3 and TRRAP, the latter of which encodes a PI3K-like protein kinase. Targeted next generation sequencing was performed on the circulating tumour DNA of 20 pts in the Phase II cohort taken before, during and after treatment to further validate these findings and to assess for other mechanisms of response or resistance. The final translational results will be presented at the meeting. Conclusions: The combination of Copanlisib and Trastuzumab is a safe and tolerable regimen and is associated with clinical efficacy in a heavily pre-treated metastatic HER2-positive breast cancer population. Translational studies may have identified novel resistance biomarkers in this pt cohort. Citation Format: Lisa Prior, Niamh M Keegan, Simon J Furney, Janice M Walshe, Giuseppe Gullo, John Crown, M John Kennedy, Diarmuid Smith, John McCaffrey, Catherine M Kelly, Keith Egan, Jennifer Kerr, Mark Given, Niall Sheehy, Peter O'Donovan, Andres Hernando, Ausra Teiserskiene, Imelda Parker, Elaine Kay, Ray McDermott, Maccon M Keane, Seamus O'Reilly, Liam Grogan, Oscar Breathnach, Patrick G Morris, Sinead Toomey, Bryan T Hennessy. Phase Ib/II trial evaluating safety and efficacy of copanlisib (PI3K inhibitor) and trastuzumab in pre-treated advanced HER2-positive breast cancer: Results from the PantHER study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-08.

Abstract P239: Safety and efficacy of copanlisib in combination with nivolumab: A phase Ib study in patients with advanced solid tumors

Abstract Introduction: Copanlisib (C) is a pan-class I PI3K inhibitor, with predominant activity against the PI3K-α and -δ isoforms, approved for patients (pts) with relapsed follicular lymphoma. The PD-1 inhibitor nivolumab (N) is approved for several advanced or metastatic solid tumors. Following preclinical demonstration of the immunomodulatory activity of C (Glaeske et al. AACR 2018), we report Phase Ib results evaluating the safety and efficacy of C+N in pts with advanced solid tumors (NCT03735628). Methods: PD-1 inhibitor-naive adult pts with advanced solid tumors received C 45 mg or 60 mg i.v. (days 1, 8, and 15; 28-day cycle) and N 240 mg (day 15 of cycle 1 and days 1 and 15 of subsequent cycles). The primary objective was determination of the recommended Phase II dose (RP2D) of C in combination with N. Secondary endpoints were safety/tolerability, pharmacokinetics (PK), and efficacy. Exploratory real-time evaluation of 77 pharmacodynamic and predictive immune cell biomarkers by flow cytometry on whole blood was performed. Results: 16 pts were treated (C 45 mg + N 240 mg, n=5; C 60 mg + N 240 mg, n=11). Median age was 65 years (range 37–89), 12 pts (75%) were male, and 8 pts (50%) had stage IV disease at diagnosis; the most common tumor types were head and neck squamous cell carcinoma (HNSCC; 7 pts) and bladder cancer (BC; 4 pts). No dose-limiting toxicities were reported. The RP2D of C+N 240 mg was 60 mg. As of 13 May 2020, 4 pts remain on treatment. The most common treatment-emergent adverse events (TEAEs) of any grade were hypertension and diarrhea (7 pts [44%] each, ≤ grade [G] 3) and maculo-papular rash and fatigue (6 pts [38%] each, ≤G3). C-related TEAEs were reported in 88% of pts, all ≤G3. AEs leading to C dose interruption/reduction were reported in 31%/19% of pts; TEAEs led to C discontinuation in 1 pt (60 mg; hematuria). Serious AEs occurred in 5 pts (31%). One G5 TEAE occurred (45 mg; general physical health deterioration, unrelated to C or N). No PK interactions were observed between C and N. Two pts had a partial response: 1 in the C 45 mg group (HNSCC) and 1 in the 60 mg group (BC; benefit sustained after 19 cycles). Stable disease was seen in 10 pts and disease progression in 3 pts; disease control rate (DCR) was 75%. Maximum decrease in circulating monocytic myeloid-derived suppressor cells (M-MDSCs; p<0.05) from baseline occurred on day 2 after C, returning to baseline on day 8. A significant increase in activated (HLA-DR+ and CD38+) natural killer and CD8+ T cells was seen 2 weeks post-treatment with C+N. Lower baseline levels of CD8+ Teffector memory (TEM) subset CD45RA-/CCR7- (CD3+/CD8+) seemed to associate with higher DCR. Conclusions: C+N showed acceptable safety and preliminary efficacy in pts with advanced solid tumors. The immunomodulatory effect of C on M-MDSCs was seen 2 days post-treatment, and lower TEM subset levels seemed to associate with better disease control. These results support further investigation of C+N in pts with advanced solid tumors. Funding: Bayer AG. Writing support: Complete HealthVizion. Citation Format: Benedito A. Carneiro, Robert Jotte, Nashat Gabrail, Omid Hamid, Funan Huang, Shalini Chaturvedi, Matthias Herpers, Lidia Mongay Soler, Barrett H. Childs, Aaron Hansen. Safety and efficacy of copanlisib in combination with nivolumab: A phase Ib study in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P239.

A Phase I Trial of PI3Kαδ Inhibitor Copanlisib in Combination with Nivolumab in Patients with Richter's Transformation (RT) or Transformed Non-Hodgkin Lymphoma (tNHL)

Background. Despite advances in targeted and cellular therapy, outcomes among patients with RT and tNHL remain dismal. Copanlisib (COPA) is a selective, small molecule, PI3K inhibitor which preferentially targets the p110αδ isoforms . COPA has shown clinical efficacy in NHL and is an approved therapy for follicular lymphoma (FL). Nivolumab is a PD-1 antagonist which has demonstrated activity in Hodgkin lymphoma as well as NHL. Furthermore, combined targeting of PI3K and PD-1 has demonstrated synergy in pre-clinical lymphoma models. Here we report initial results of a phase 1 study of COPA in combination with nivolumab in patients with R/R RT or tNHL (NCT03884998).Methods. This ongoing multicenter, open-label, phase I, investigator-sponsored study is enrolling patients with RT or tNHL, age ≥18 years, whose disease had relapsed or was refractory to ≥1 prior line of therapy. The phase I portion of the study followed a standard 3+3 design with three planned dose levels of COPA administered IV (dose level [DL]1 - 45 mg on days 1, 8 and 15; DL2 - 60 mg on days 1, 8 and 15; DL “-1” - 45 mg on days 1 and 15 of a 28-day cycle). Nivolumab 240 mg was given IV on days 1 and 15. Patients received up to 24 cycles of therapy. The primary study objective was to evaluate the maximum tolerated dose (MTD) of the combination; secondary objectives included preliminary measures of efficacy by Lugano criteria including PET/CT scans. Exploratory objectives included pharmacodynamic endpoints. Dose limiting toxicities (DLT) were defined as grade ≥4 hematologic > 7 days or grade ≥3 non-hematologic toxicities.Results. Of the eleven patients enrolled, 8 had RT and 3 had transformed FL (tFL); 91% (10/11) were men. Median age was 70 (43-77) years, 82% (9/11) had an ECOG performance status ≤1. Patients had received a median of 3 prior lines of therapy (range, 1-8), including three patients (1 RT, 2 FL) who had undergone CAR T cell therapy. Eight patients were treated at DL1 (45 mg COPA), of which 2 patients did not complete the DLT period due to rapidly progressive disease and were replaced. No DLTs were observed at this dose level. At DL2 (60 mg COPA), three DLTs (grade 4 febrile neutropenia and grade 4 thrombocytopenia in another patient) were observed among the three patients treated. Therefore, the MTD and recommended phase 2 dose (RP2D) of COPA in combination with nivolumab was determined to be 45 mg on days 1, 8, 15. The most common treatment-related adverse events (AEs, any grade) were anemia and neutropenia (Table 1). Five pts discontinued therapy due to progressive disease; one due to intercurrent infection (coccidiomycosis, unrelated to study drugs), two due to DLTs noted above. Three patients remain on treatment. Among the seven efficacy-evaluable patients who completed at least one cycle of therapy, median time on treatment was 2 months (range, 2-9 months). Of these, four patients achieved a response per the investigators' assessment (tFL: 2 partial responses; RT: 1 complete response and 1 partial response). Efficacy assessment is ongoing and will be reported at the meeting.Discussion. We identified COPA 45 mg IV on days 1, 8 and 15 as the MTD/RP2D in combination with nivolumab in patients with R/R RT and tFL. This combination was well-tolerated at the MTD/RP2D, and the study is currently enrolling patients in an expansion cohort to further characterize the efficacy of this regimen. [Display omitted] DisclosuresShouse: Beigene Pharmaceuticals: Honoraria; Kite Pharmaceuticals: Speakers Bureau. Siddiqi: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Juno therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Other: DSM Member, Speakers Bureau; PCYC: Speakers Bureau; Jannsen: Speakers Bureau; Dava Oncology: Honoraria; ResearchToPractice: Honoraria. Popplewell: Pfizer: Other: Travel; Novartis: Other: Travel; Hoffman La Roche: Other: Food. Kittai: Janssen: Consultancy; Bristol-Meyers Squibb: Consultancy; Abbvie: Consultancy. Davids: MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; AbbVie: Consultancy; BeiGene: Consultancy; Merck: Consultancy; Ascentage Pharma: Consultancy, Research Funding; Eli Lilly and Company: Consultancy; BMS: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy; Astra-Zeneca: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Research to Practice: Consultancy; Verastem: Consultancy, Research Funding; Takeda: Consultancy; MEI Pharma: Consultancy; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Danilov: Genentech: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; Rigel Pharm: Honoraria; Takeda Oncology: Research Funding; Bayer Oncology: Consultancy, Honoraria, Research Funding; Gilead Sciences: Research Funding; Pharmacyclics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Research Funding.

Feasibility of Combining the Phosphatidylinositol 3-Kinase Inhibitor Copanlisib With Rituximab-Based Immunochemotherapy in Patients With Relapsed Indolent B-cell Lymphoma

BackgroundWhen treating indolent B-cell lymphoma, combining continuously administered oral phosphatidylinositol 3-kinase (PI3K) inhibitors with immunochemotherapy has been associated with toxicity. CHRONOS-4 (Phase III; NCT02626455) investigates the intravenous, intermittently administered pan-class I PI3K inhibitor copanlisib in combination with rituximab plus bendamustine (R-B) or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with relapsed indolent B-cell lymphoma. We report safety run-in results. Patients and MethodsPatients aged ≥18 years with relapsed CD20-positive indolent B-cell lymphoma received copanlisib (45 mg, increasing to 60 mg if no dose-limiting toxicities) weekly on an intermittent schedule with R-B or R-CHOP. Primary objective was to identify a recommended Phase III dose (RP3D). We also assessed objective response, safety, and tolerability. ResultsTen patients received copanlisib plus R-B and 11 received copanlisib plus R-CHOP. No dose-limiting toxicities were reported; RP3D was 60 mg. All patients had ≥1 treatment-emergent adverse event (TEAE), most commonly (all grade/grade 3/4) for copanlisib plus R-B: decreased neutrophil count (80%/50%), nausea (70%/0%), decreased platelet count (60%/10%), hyperglycemia (60%/50%); for copanlisib plus R-CHOP: hyperglycemia (82%/64%), hypertension (73%/64%), decreased neutrophil count (64%/64%). Two and 8 patients had serious TEAEs with copanlisib plus R-B and R-CHOP, respectively. Among evaluable patients, objective response rates were 90% (5 complete, 4 partial) and 100% (3 complete, 7 partial) with copanlisib plus R-B and R-CHOP, respectively. ConclusionCopanlisib is the first PI3K inhibitor to demonstrate safe, tolerable, and effective combinability with immunochemotherapy in patients with relapsed indolent B-cell lymphoma at full dose (60 mg). Further evaluation is ongoing.

Abstract CT222: BrUOG360: A phase Ib/II study of copanlisib combined with rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC)

Abstract Background: Patients with metastatic prostate cancer invariably progress to a lethal state called metastatic castration-resistant prostate cancer (mCRPC). Approximately 23-28% of patients with mCRPC have molecular alterations in genes associated with homologous recombination (HR) DNA repair mechanisms (e.g., BRCA1/2). These alterations are associated with sensitivity to poly ADP-ribose polymerase inhibitors (PARPi). The responses to PARPi can be short-lived, and several mechanisms of resistance have been described. Preclinical studies demonstrated that PI3K suppression impairs HR and sensitizes cancer cells to PARPi even in the absence of mutations in DNA repair genes. The synergy between olaparib and PI3K inhibition led to marked tumor regression both in vitro and in vivo models of prostate cancer. These preclinical results, coupled with the importance of both the PI3K pathway and DNA damage repair mechanisms in mCRPC, support our hypothesis that dual inhibition of PI3K and PARP might improve clinical outcomes in mCRPC. We describe an ongoing phase Ib/II study aimed to evaluate the safety and determine the maximum tolerated dose (MTD) of the combination of copanlisib (pan-class I PI3K inhibitor) and rucaparib (a PARP-1, -2 and -3 inhibitor) followed by an expansion cohort exploring efficacy among patients with mCRPC. Methods: Phase I, dose-escalation part of the study, aims to establish the MTD and/or recommended phase II dose (RP2D) of copanlisib in combination with rucaparib. Dose escalation will follow a standard 3+3 escalation scheme. Evidence of HR-deficiency is not required to enroll in phase I, but is for phase II. All subjects will be treated with rucaparib (continuous oral administration twice daily) 400mg (dose level I), 500mg (II) or 600mg (III-IV) and intravenous copanlisib (D1, D8, D15; 28-day cycle; dose levels I-III: 45 mg; level IV: 60 mg). Once the RP2D of copanlisib and rucaparib in the phase I part of the study is determined, enrollment will commence into the phase II part of the trial. The primary objective of phase II is to estimate the preliminary efficacy of the combination of copanlisib and rucaparib among subjects with mCRPC carrying mutations in DNA repair genes, as measured by prostate-specific antigen (PSA) response. Up to 20 patients will enroll in the phase II using a Simon's two-stage design. In the first stage, 14 patients will be accrued. If there are 7 or fewer PSA responses in these 14 patients, the study will be stopped for futility. Otherwise, an additional 6 patients will be accrued. Patients with mCRPC need to have had disease progression during treatment with abiraterone, enzalutamide, and/or apalutamide. Prior therapy with taxanes is allowed. Translational objectives include the correlation of clinical outcomes with HR mutations and PI3K/mTOR pathway gene alterations in the tumor. Genomic analyses will also investigate biomarkers and mechanisms of action of the combination. The clinical trial is recruiting (NCT04253262). Citation Format: Andre De Souza, Rahul Aggarwal, Howard Safran, Dragan Golijanin, Roxanne Wood, Adam Olszewski, Wafik S. El-Deiry, Anthony Mega, Benedito A. Carneiro. BrUOG360: A phase Ib/II study of copanlisib combined with rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT222.

A phase II study of the PI3K inhibitor copanlisib in combination with the anti-CD20 monoclonal antibody rituximab for patients with marginal zone lymphoma: treatment rationale and protocol design of the COUP-1 trial

BackgroundAdvanced stage marginal zone lymphoma (MZL) is an incurable indolent B-cell lymphoma, for which a wide variety of treatments ranging from single agent rituximab to more dose intense immunochemotherapy exists. One of the major goals in this palliative setting is to develop chemotherapy-free treatments, which approach the efficacy of immunochemotherapies, but avoid chemotherapy associated toxicity in this often elderly patient population. The PI3K inhibitor copanlisib has recently shown remarkable clinical activity in refractory or relapsed indolent B–cell lymphomas, among them MZL. Based on these data, copanlisib monotherapy was granted breakthrough designation by the FDA for the treatment of adult patients with relapsed marginal zone lymphoma who have received at least two prior therapies. However, data are still limited in particular for MZL. Based on this, the COUP-1 trial aims at testing the toxicity and efficacy of copanlisib in combination with rituximab in treatment naive and relapsed MZL.MethodsCOUP-1 is a prospective, multicenter, single-arm, open-label, non-randomized phase II trial of 6 cycles (28 days cycle) of copanlisib (60 mg intravenous day 1, 8, 15) and rituximab (375 mg/m2 intravenous day 1) in the induction phase followed by a maintenance phase of copanlisib (d1, d15 every 4 weeks for a maximum of 12 cycles) and rituximab (d1 every 8 weeks for a maximum of 12 cycles) in patients aged ≥18 years with previously untreated or relapsed MZL in need of treatment. A total of 56 patients are to be enrolled. Primary endpoint is the complete response (CR) rate determined 12 months after start of induction therapy. Secondary endpoints include the overall response (OR) rate, progression free survival (PFS), overall survival (OS), safety and patient related outcome with quality of life.The study includes a translational bio-sampling program with the prospect to measure minimal residual disease. The study was initiated in November 2019.DiscussionThe COUP-1 trial evaluates the efficacy and toxicity of the treatment of copanlisib in combination with rituximab in patients with MZL and additionally offers the chance for translational research in this heterogenous type of lymphoma.Trial registrationClinicalTrials.gov: NCT03474744. Registration date: 03/23/2018.

Inhibition of PI3K Alpha and PI3K Delta with Copanlisib Shows Preclinical Activity As a Single Agent and in Combination in Multiple Myeloma

Background: The reversible, pan-class I PI3K inhibitor, copanlisib (BAY 80-6946), has preferred activity for the alpha and delta isoforms. This is in contrast to the delta and delta/gamma isoform-selective PI3K inhibitors developed primarily for Non-Hodgkin Lymphoma. We hypothesize that a copanlisib-based combination strategy could provide an effective, novel therapy for multiple myeloma with a pharmacodynamic biomarker to identify patients most likely to benefit from the therapy. Here we demonstrate the preclinical efficacy of copanlisib as a single agent and in combination with carfilzomib, a BET bromodomain inhibitor (BETi) and venetoclax.Methods: A panel of 20 human multiple myeloma (MM) cell lines were evaluated for the effects of copanlisib on cell proliferation after a 5-day exposure to the drug. Sensitive NCI-H929, MM.1S, L-363, and resistant AMO-1, JJN3, COLO-677 MM cell lines were selected for further analysis. All mechanism of action (MOA) studies were performed by treating the MM cells at a dose of 100 nM copanlisib. Cell cycle analysis and induction of apoptosis was performed by FACS after propidium iodide or Annexin V FITC staining respectively on cells treated for 72 hours. Reverse phase protein array (RPPA) was performed at baseline and post treatment for proteomic analysis with confirmatory western blots. Phospho-flow was performed to measure pre- and post-treatment levels of the ribosomal protein phospho-S6 (p-S6). The combination studies utilized serial dilutions of copanlisib with carfilzomib, a BETi, and venetoclax. Excess over highest single agent (EOHSA) was used to evaluate for potentiation. These findings were confirmed in vivo using a SCID mouse model.Results: Following copanlisib exposure, we observed apoptosis in the sensitive cell lines (50-80% AN-V+ cells) but not in resistant cell lines (1-5% AN-V+ cells). We saw an increased cell cycle arrest in G1 in the sensitive cell lines, but not in the resistant cell lines. RPPA performed at baseline revealed a pattern of low p-S6 at the serine positions 235/236 and 240/244 in sensitive compared to resistant cell lines. Western blot analyses validated the RPPA results. We next performed RPPA following exposure to copanlisib, which resulted in a greater decrease in p-S6 in the sensitive cell lines NCI-H929 and L363 (53-83%, 73-93% respectively) compared to resistant cell lines COLO-677 and JJN3 (5-27%, and 38-67%, respectively). The pharmacodynamic p-S6 response was maintained following 24hr and 48hr of drug exposure. These findings were further supported with western blot analysis and phospho-flow. Treatment with copanlisib in combination with carfilzomib or BETi showed potentiation by EOHSA statistics, but this was not seen in with venetoclax. In xenograft models, treatment with copanlisib 10mg/kg by tail vein injection twice daily every 7 days resulted in regression of tumor growth compared to vehicle control. In the L-363 xenograft model, single agent copanlisib resulted in greater tumor regression than single agent carfilzomib.Discussion: Copanlisib demonstrated pre-clinical anti-tumor activity as a single agent and in combination with conventional and novel agents in vitro and in vivo . The low nanomolar range IC50 values correlated with low baseline and post-treatment p-S6, which may allow for the development of a pharmacodynamic FACS based biomarker assay to select patients most likely to benefit from a copanlisib based combination therapy. DisclosuresSlamon:Pfizer: Equity Ownership, Honoraria, Research Funding; Eli Lilly: Consultancy; Bayer: Consultancy; Biomarin: Consultancy, Equity Ownership; Novartis: Honoraria, Research Funding.

Copanlisib for the Treatment of Malignant Lymphoma: Clinical Experience and Future Perspectives.

Dysregulation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin signaling is common in both indolent and aggressive forms of malignant lymphoma, for which several targeted therapies have been developed. Copanlisib is a highly selective and potent intravenous pan-class I PI3K inhibitor that has demonstrated durable objective responses and a manageable safety profile in heavily pre-treated patients with indolent lymphomas. As a result, copanlisib monotherapy received accelerated approval from the US Food and Drug Administration for the treatment of adults with relapsed follicular lymphoma who have received at least two systemic therapies, and breakthrough designation for patients with pre-treated relapsed or refractory marginal zone lymphoma. Hyperglycemia and hypertension are among the most frequently reported adverse events with copanlisib monotherapy, and are infusion-related, transient, and manageable with standard therapies. Mild diarrhea is also a common adverse event with copanlisib monotherapy; there is no evidence of worsening severity of diarrhea, or serious gastrointestinal toxicities such as colitis or severe liver enzyme elevations, which have been reported with orally administered PI3K inhibitors. The intravenous route of administration and intermittent dosing schedule of copanlisib may support a favorable tolerability profile over continually administered oral alternatives. Ongoing studies of copanlisib in combination with rituximab and standard-of-care chemotherapy in patients with relapsed indolent lymphoma have the potential to support the use of copanlisib in the second-line setting, providing a much-needed additional therapeutic option in this underserved patient population.

Abstract OT-34-01: Phase Ib/II trial of copanlisib in combination with trastuzumab and pertuzumab after induction treatment of HER2 positive metastatic breast cancer with PIK3CA mutation or PTEN mutation

Abstract Background:The PI3K/Akt/mTOR pathway is a critical regulator of cell growth, survival, and metabolism in cancer. Its activation plays an important role in resistance to chemotherapy and HER2 targeted therapy. PIK3CA activating mutations and PTEN loss were reported in 30% and 16% of BOLERO-1 and 32% and 12% of BOLERO-3 patients, respectively. Exploratory analyses suggested that the addition of everolimus to trastuzumab and chemotherapy improved progression free survival (PFS) in patients with PIK3CA mutations and PTEN loss. In the phase III CLEOPATRA trial, while the combination of pertuzumab (P) plus trastuzumab (H) plus docetaxel (T) as compared with trastuzumab (H) plus docetaxel (T), significantly prolonged PFS (18.5 vs 12.4 months) for first-line treatment for HER2-positive (+ve) metastatic breast cancer (MBC), longer median PFS was observed in patients with wildtype versus mutated PIK3CA in both the control (13.8 v 8.6 months) and pertuzumab groups (21.8 v 12.5 months). Copanlisib is a highly selective, class 1 pan-PI3K inhibitor with predominant activity against both the δ and α isoforms. It is currently FDA approved for the treatment of adults with relapsed follicular lymphoma. This study hypothesizes that the addition of copanlisib to dual HER2 targeted therapy after first line induction treatment will improve clinical outcomes in HER2 positive MBC patients with PIK3CA or PTEN genomic alterations. Trial Design: This is a randomized, two- arm, open label, phase-2 study to evaluate the clinical activity of copanlisib added to HP maintenance after induction with THP in HER2 +ve MBC patients with PIK3CA mutations or PTEN loss. A safety run-in cohort (phase 1B) will be performed. Copanlisib will be administered weekly on D1, D8 of a 21-day cycle. Eligibility criteriaHER2 +ve MBC based on ASCO-CAP criteria (HER2 status based on metastatic tissue)• Activating mutations in PIK3CA, or PTEN loss• ECOG performance status ≤1• Normal organ and marrow function• Within 8 weeks of completion of first-line induction therapy with THP (Phase-2). Any prior treatment provided eligible to receive THP induction (Phase-1B) Specific aimsTo assess the benefit of adding copanlisib to HP in HER2+ve MBC patients with PIK3CA mutations or PTEN loss after induction treatment (Phase-2)• To determine safety and recommended phase 2 dose (RP2D) of copanlisib, HP combination in HER2 MBC patients (Phase-1B)• To correlate PFS and OS with the triplet combination with the number of induction cycles, hormone receptor status, and PTEN loss by IHC• To identify potential predictive and prognostic biomarkers for copanlisib activity Statistical methodsThe primary objective of the phase-1B portion is to determine the RP2D for the combination of copanlisib, trastuzumab, and pertuzumab. Phase 1 portion will use a 3+3 dose de-escalation design. The primary objective of the phase 2 portion is to determine a difference in PFS with the addition of copanlisib to HP maintenance after induction. Projected median PFS in control group is 8 months and 16 months in the experimental arm. We aim to detect a HR of 0.50 with power of 0.90 with 1-sided alpha of 0.1. With a sample size of 82, 12 months post-accrual follow-up, and accrual rate of 5 patients per month, the study duration is 30 months. To have 82 evaluable patients with a 15% drop-out rate, we would need to enroll 96 patients. A Wieand rule futility interim analysis will be conducted when half of the total of 54 required PFS events are observed. Citation Format: Senthil Damodaran, Rashmi K Murthy, Maliha Nusrat, Babita Saigal, Samantha C Trager, Debu Tripathy, Funda Meric-Bernstam. Phase Ib/II trial of copanlisib in combination with trastuzumab and pertuzumab after induction treatment of HER2 positive metastatic breast cancer with PIK3CA mutation or PTEN mutation [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-34-01.