Phase 1b Results Research Articles

CD22 CAR T cells demonstrate high response rates and safety in pediatric and adult B-ALL: Phase 1b results.

Chimeric antigen receptor (CAR) T cells targeting CD22 (CD22-CAR) provide a therapeutic option for patients with CD22+ malignancies with progression after CD19-directed therapies. Using on-site, automated, closed-loop manufacturing, we conducted parallel Phase 1b clinical trials investigating a humanized CD22-CAR with 41BB costimulatory domain in children and adults with heavily treated, relapsed/refractory (r/r) B-ALL. Of 19 patients enrolled, 18 had successful CD22-CAR manufacturing, and 16 patients were infused. High grade (3-4) cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS) each occurred in only one patient; however, three patients experienced immune-effector-cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Twelve of 16 patients (75%) achieved CR with an overall 56% MRD-negative CR rate. Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.

Abstract B045: Ataxia telangiectasia- and Rad3-related kinase inhibitor (ATRi) camonsertib in combination with low dose gemcitabine in patients with solid tumors with DNA damage response (DDR) aberrations: Preclinical and Phase 1b results

Abstract Background: Antitumor activity and good tolerability of camonsertib (cam) monotherapy in patients (pts) with recurrent solid tumors was previously reported. Preclinical data showed that cam-related tumor cell death is potentiated by the replication stress-inducing agent gemcitabine (gem) even at low doses, resulting in synergistic combination activity. We evaluated safety/tolerability and efficacy of cam+gem in this Ph1b trial (TRESR; NCT04497116). Methods: A tumor xenograft (Granta-519; ATM loss of function) was tested with a range of cam+gem doses. Pts >18yr, ECOG 0-1, with advanced solid tumors with deleterious DDR alterations were enrolled. Cam (80-120mg) + de-escalating gem doses (1000-100mg/m2) were given over 21- or 28-day (d) cycles (cam d1-2/3 and d8-9/10 or d15-16/17; gem d1 and d8 or d15). Dose decisions followed BOIN methodology. Endpoints were safety/tolerability, recommended Ph2 dose (RP2D), response rate (RECIST v1.1, CA-125 [GCIG], or PSA [PCWG3]), clinical benefit rate (CBR; response or treatment [Tx] duration ≥16 weeks [w] without progression), ctDNA molecular response rate (MRR; best reduction in mean variant allele frequency ≥50%), and cam PK. Replication stress markers were analyzed in surrogate normal tissue. Results: In a tumor xenograft model, low doses of cam (1/3 of maximum tolerated dose [MTD]) and gem (1/20 of MTD) resulted in tumor regression not observed in single agent arms, with good tolerability. As of May 2023, 54 pts were treated with cam+gem in TRESR (ovarian [n=19], pancreatic [n=8], breast [n=6], other [n=21] tumors); enrollment genes included ATM (n=12), BRCA1 (n=18), BRCA2 (n=16), other (n=8). No drug-drug interactions were noted. RECIST v1.1 or CA-125 responses were observed in 5 pts (40 evaluable): 3 cPR, 1 uPR in pts with ovarian (n=2; 1 ATM, 1 BRCA1), endometrial (gPALB2), and breast (gBRCA1) cancers; 1 CA-125 response in a pt (ovarian/gBRCA1) with SD (on Tx 21w+). Four additional pts (uterine carcinosarcoma, ovarian, liver, lung) with SD were on Tx ≥6 months. CBR was 42.4% (14/33) in evaluable pts and 66.7% (8/12) in pts with gynecological cancers. MRR was 58% (7/12) in evaluable pts. Myelotoxicity, the most frequent Tx-related toxicity, improved with decreasing gem doses. Responses were maintained in the 3 pts with cPR following reductions to ≤200mg/m2 gem; the pts with the uPR and CA-125 responses started Tx at 200 and 100mg/m2 gem, respectively. Preliminary RP2D is 80mg cam (50% of monotherapy RP2D) + 400mg/m2 gem, 28d cycle (1w on/1w off). Related Grade 3+ neutropenia, anemia, and thrombocytopenia occurred in 44%, 11%, and 0% pts, respectively (n=9). Importantly, neutrophil nadir occurred in the 1w off Tx with quick rebound, alleviating the need for dose modifications. Conclusion: The synergy of low doses of cam+gem, demonstrated in preclinical studies, was confirmed in the clinical setting. A safe and tolerable dose and schedule of the combination was identified. The antitumor efficacy supports further development in pts with gynecological cancers; evaluation at RP2D is ongoing. Citation Format: Ezra Rosen, Timothy A Yap, Elisa Fontana, Elizabeth K Lee, Devalingam Mahalingam, Martin Højgaard, Niharika B Mettu, Gregory M Cote, Ruth Plummer, Ian M Silverman, Joseph D Schonhoft, Emeline Bacque, Adrian J Fretland, Gabriela Gomez, Danielle Ulanet, Kezhen Fei, Julia Yang, Maria Koehler, Anne Roulston, Li Li, Michal Zimmermann, Benedito A Carneiro, Stephanie Lheureux. Ataxia telangiectasia- and Rad3-related kinase inhibitor (ATRi) camonsertib in combination with low dose gemcitabine in patients with solid tumors with DNA damage response (DDR) aberrations: Preclinical and Phase 1b results [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B045.

Pharmacokinetics, Drug Interaction, and Exposure-Safety Analyses of Tazemetostat When Co-Administered with Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma: Phase 1b Results of Symphony-1

Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved in the US for the treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL) whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies or who have no satisfactory alternative treatment options. EZH2 modulates the B-cell tumor microenvironment, supporting combination approaches to treatment. SYMPHONY-1 (EZH-302; NCT04224493) is a Phase 1b/3 study designed to determine the phase 3 dose (RP3D), pharmacokinetics, efficacy, and safety of TAZ + lenalidomide and rituximab (R 2) in patients with R/R FL after ≥1 prior therapy. We report here the pharmacokinetics; drug interaction, and exposure-safety analysis of TAZ in combination with R 2, which are used to support the dose selection for RP3D. Methods: Phase 1b evaluated TAZ at 3 dose levels (400, 600, and 800 mg, bid) in 28-day cycles with standard-dose R 2. Primary endpoints of the Phase 1b portion were safety and determination of the recommended phase 3 dose (RP3D). PK of Taz and drug-drug interaction (DDI) with R 2 were also evaluated. The AEs Grade 3 or greater of treatment emergent AE (TEAE3), gastro-intestinal AE (GIAE3), neutropenia (NEU3), hepatotoxic event (HEP3), anemia (ANEM3) and thrombosis (THRM3) were assessed, and their relationships with Taz exposure when combined with R 2 were explored. Results: The PK results are based on thirty-nine (39) patients with no major protocol deviations. TAZ PK are characterized by rapid absorption with a Tmax 1.00 hours; and a short half-life which ranged from 3.2 to 3.8 hours across all dose levels. Both Cmax and AUC increased with increasing Taz doses over the dose range. Exposures of 800 mg TAZ at steady state are similar to those found in TAZVERIK Prescribing Information. These results suggest that the PK of TAZ doses 400 mg to 800 mg BID are not altered by concomitant administration of a daily oral dose of 20 mg lenalidomide. Lenalidomide PK (Cmax and AUC) are similar to those found in Revlimid FDA's Biopharm Review (fda.gov). Taken together these data suggest there is no DDI when TAZ is given in combination with R 2. The Taz exposure at 800 mg bid in the presence of R 2 is over the target engagement of > 80%. No clear increasing AE trend with increasing exposure (AUC) was observed with TEAE3. More importantly, there is no increasing trend of other AEs of gastro-intestinal AE (GIAE3), neutropenia (NEU3), hepatotoxic event (HEP3), and thrombosis (THRM3) with increasing exposure (AUC) or dose was observed. However, there is no ANEM3 observed with the available database. Conclusions: TAZ + R 2 combination demonstrates consistent and unaltered PK for TAZ and lenalidomide, and delivered an optimal target engagement, and favorable safety profile. There is no DDI when TAZ is given in combination with R 2. The exposure safety analysis demonstrated that there were no obvious trends in increasing Grade ≥3 AEs with increasing exposure when combined with R 2. Based on the totality of the PK, target engagement and exposure-safety analysis, the RP3D of TAZ was determined to be 800 mg BID in combination with R 2. The 2-arm randomized phase 3 portion is currently ongoing to further explore the efficacy and safety of TAZ 800 mg + R 2 in ≈500 patients with R/R FL who completed ≥1 prior systemic therapy.

AK117 (anti-CD47 monoclonal antibody) in Combination with Azacitidine for Newly Diagnosed Higher Risk Myelodysplastic Syndrome (HR-MDS): AK117-103 Phase 1b Results

Background: CD47, an immune checkpoint overexpressed by tumor cells, plays a crucial role in evading the antitumor immune response. AK117, an IgG4 monoclonal antibody (mAb) targeting CD47, has emerged as a potential best-in-class therapy with high affinity binding to CD47 and without inducing hemagglutination effects. By blocking CD47, AK117 effectively triggers macrophage-mediated phagocytosis of hematological malignancy cells, and in combination with azacitidine (AZA), it synergistically enhances the activation of “eat me” signals. In this study, we present the Phase 1b data from the AK117-103 study conducted in patients with newly diagnosed higher risk myelodysplastic syndrome (HR-MDS). Methods: Eligible patients with newly diagnosed intermediate/high/very high-risk MDS, determined by the Revised International Prognostic Scoring System (IPSS-R) prognostic risk score >3, were enrolled to receive combination therapy with AK117 and AZA. AK117 was administered intravenously (IV) following various dosing regimens (20-30 mg/kg once weekly [QW], or 20-45 mg/kg every 2 weeks [Q2W], or 30 mg/kg every 4 weeks [Q4W]), whereas AZA was administered subcutaneously (SC) at the standard dosage (75 mg/m 2, Day 1-7, Q4W). The primary endpoints of this study were safety/tolerability and the complete remission (CR) rate based on the International Working Group (IWG) 2006 response criteria. Results: As of June 9, 2023, 72 patients were enrolled (median age: 66 years, 69.4% males). Most patients exhibited abnormal hematologic conditions at baseline, including decreased hemoglobin, neutrophil count, and platelet count. Specifically, 69.4% of patients had Grade ≥3 anemia, 61.1% had Grade ≥3 neutrophil count decrease, and 47.2% had Grade ≥3 platelet count decrease. For the recommended phase 2 dose (RP2D) group, treated with a combination of AK117 30 mg/kg Q2W and AZA, 30 patients were enrolled with a median age of 67 years, 80.0% of whom were males. According to IPSS-R risk assessment, 33.3%, 23.3%, and 43.3% of patients had intermediate, high, and very high risk, respectively. 30.0% of patients had poor-risk cytogenetics, with 23.0% of those being complex. After a median follow-up of 6.6 months (ranging from 0.4-17.2 months), anemia (a primary adverse event associated with CD47 blocking antibodies) occurred in 30.6% (22/72) of the patients, of which Grade ≥ 3 anemia accounted for 22.2% (16/72). Other commonly observed treatment-emergent adverse events (TEAEs) (≥30%) included decreased neutrophil count (77.8%), decreased white blood cell count (72.2%), decreased platelet count (69.4%), pyrexia (58.3%), decreased lymphocyte count (41.7%), constipation (41.7%), and vomiting (31.9%). Three patients (4.2%) discontinued treatment due to TEAEs. The efficacy of AK117 was compared at different dosages, and ultimately, 30mg/kg Q2W was chosen as the RP2D. As of June 21, 2023, among 27 evaluable patients, the CR rate was 48.1%. 8 patients achieved marrow CR (5 also with hematologic improvement [HI]), and 2 patients achieved HI alone. Among 24 evaluable patients with ≥ 3 months follow-up, the CR rate further escalated to 54.2%. Of 13 evaluable patients who initially required red blood cells (RBC) transfusions, 8(61.5%) became independent of RBC transfusion. Conclusions: AK117 in combination with AZA was well tolerated with low incidence of anemia and demonstrated promising efficacy in patients with newly diagnosed HR-MDS.

Tazemetostat in Combination with Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma: Updated Phase 1b Results of Symphony-1 with 22.5 Months Follow-up

Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL) whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies, or patients with R/R FL who have no satisfactory alternative treatment options. We previously reported the efficacy and safety of TAZ in combination with lenalidomide and rituximab (R 2) in patients with R/R FL from the SYMPHONY-1 study (EZH-302; NCT04224493) after complete enrollment and following the phase 1b safety run-in period. Here, we report the updated efficacy and safety results after a median follow-up of 22.5 months. Methods: Phase 1b evaluated TAZ at 3 dose levels (400, 600, and 800 mg orally twice daily [BID]) in 28-day cycles with standard-dose R 2. After the initial 12 months of combination therapy, tazemetostat 800 mg BID was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Primary endpoints of the phase 1b portion were safety and determination of the recommended phase 3 dose (RP3D). Secondary endpoints included pharmacokinetic (PK) parameters. Efficacy analysis was performed on the intent-to-treat (ITT) population, including best overall response, progression-free survival (PFS), and duration of response (DOR) per investigator assessment, according to Lugano 2014 response criteria. Results: As of July 10, 2023, 44 patients were enrolled and receiving TAZ + R 2 (400 [n=6], 600 [n=19], or 800 mg [n=19]). Median age was 67 years, 31.8% of patients had received >1 prior therapy, and patients had a median of 1 prior line of therapy (range, 1-4). Overall, 81.8% (n=36) of patients had wild-type (WT) EZH2 FL, 34.1% (n=15) of patients had rituximab-refractory disease, and 27.3% (n=12) of patients had POD24. Median durations of treatment exposure for TAZ, lenalidomide, and rituximab were 13.3, 10.8, and 4.6 months, respectively. In the 800-mg cohort, the median relative dose intensity was 94.1%, 92.9%, and 100% for TAZ, lenalidomide, and rituximab, respectively. No dose-limiting toxicities were observed in phase 1b, and no new safety signals were identified as of the data cutoff. The RP3D of TAZ was determined to be 800 mg BID in combination with R 2. The most common grade 3-4 TEAE was neutropenia (40.9%; n=18). The most frequent type of dose modification due to TEAEs for any study treatment was drug interruption (70.5%), followed by dose reduction (38.6%) and treatment discontinuation (20.5%); protocol-mandated dose modifications included simultaneous dose interruption and/or reduction of TAZ and lenalidomide for neutropenia and thrombocytopenia. Of the 44 patients, 42 patients were evaluable for tumor assessment and 2 patients had no postdose tumor assessments. Of 42 patients evaluable for tumor assessment, 23 (54.8%) had a complete response, 17 (40.5%) had a partial response, and 2 (4.8%) had stable disease. The ORR in the ITT population was 90.9% (n=40/44). The ORRs in patients with WT EZH2 and MT EZH2 were 88.9% (n=32/36) and 100% (n=7/7), respectively. The ORR in patients with rituximab-refractory disease was 93.3% (n=14/15) and in patients with POD24 was 91.7% (n=11/12). With a median follow-up of 22.5 months, median PFS and median DOR were not reached. In the ITT population, 18-month PFS and DOR estimates were 79.5% and 81.0%, respectively; in the 800-mg cohort (n=19), 18-month PFS and DOR estimates were 94.4% and 100%, respectively. PFS appeared to be dose dependent, with durable response in the 800-mg cohort. Conclusions: The safety profile of TAZ + R 2 combination therapy was consistent with previous reports, with no new safety signals identified in the phase 1b data of this study. The 12 months of initial combination therapy resulted in long-lasting remission. Dose-dependent response was seen with durable response in patients receiving TAZ 800 mg, regardless of their mutation status. The 2-arm randomized phase 3 portion will further explore the efficacy and safety of TAZ 800 mg + R 2 in ≈500 patients with R/R FL who completed ≥1 prior systemic therapy.

Tazemetostat in Combination with Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma: Phase 1b Results of Symphony-1

Background: The preferred second-line treatment for patients with relapsed/refractory (R/R) follicular lymphoma (FL) is either lenalidomide in combination with rituximab (R2) or an anti-CD20 antibody in combination with chemotherapy/immunotherapy. Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved by the US Food and Drug Administration for the treatment of patients with R/R FL whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies or who have no satisfactory alternative treatment options. EZH2 modulates the B-cell tumor microenvironment, supporting combination approaches to treatment. SYMPHONY-1 (EZH-302; NCT04224493) is a phase 1b/3 study designed to determine the recommended phase 3 dose (RP3D), efficacy, and safety of TAZ + lenalidomide and rituximab (R2) in patients with R/R FL after ≥1 prior therapy. We report the results after complete enrollment of the phase 1b safety run-in to assess safety and clinical activity of TAZ when administered with R2, including data for subsets of patients by mutation status, rituximab-refractory disease, and progression of disease in 24 months (POD24). Methods: Patients aged ≥18 years with histologically confirmed FL grade 1-3A who were previously treated with ≥1 prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy were enrolled. The phase 1b portion enrolled patients regardless of EZH2 mutation status. Phase 1b evaluated TAZ at 3 dose levels (400, 600, and 800 mg orally twice daily [BID]) in 28-day cycles with standard-dose R2. Protocol-mandated dose modifications included simultaneous dose interruption and/or reduction of TAZ and lenalidomide for grade 3 neutropenia and thrombocytopenia. Primary endpoints of the phase 1b portion were safety and determination of the RP3D. Secondary endpoints included pharmacokinetic (PK) parameters. Preliminary efficacy analysis was performed on the response-evaluable population, including best overall response, progression-free survival (PFS), and duration of response (DOR) per investigator assessment, according to Lugano 2014 response criteria. Results: As of June 14, 2022, 44 patients were enrolled and receiving TAZ + R2 (400 [n=6], 600 [n=19], and 800 mg [n=19]). Median age was 67 years, and 31.8% of patients had received >1 prior therapy. Overall, 35/42 patients (83.3%) had wild-type (WT) EZH2 FL. Patients with high-risk disease include 15 patients (34.1%) with rituximab-refractory disease and 12 patients (27.3%) with POD24 disease. Median duration of treatment exposure of tazemetostat was 9.1 months. No dose-limiting toxicities were observed in phase 1b, and no new safety signals were identified as of the data cutoff. The PK of TAZ at all dose levels was not altered by concomitant administration of daily oral lenalidomide 20 mg, and the PK of lenalidomide was not altered by concomitant administration of any of the TAZ doses. The RP3D of TAZ was determined to be 800 mg BID in combination with R2. The most common grade 3-4 TEAE was neutropenia (n=15; 34.1%). The most frequent type of dose modification due to TEAEs for any study treatment was drug interruption (n=30; 68.2%). In the 800-mg cohort, the median dose intensity was 98%, 93%, and 100% for tazemetostat, lenalidomide, and rituximab, respectively. Of 41 patients evaluable for tumor assessment, 21 (51.2%) had a complete response, 19 (46.3%) had a partial response, and 1 (2.4%) had stable disease. The overall response rate (ORR) in the response-evaluable population was 97.6% (n=40). The ORRs in patients with WT EZH2 and MT EZH2 were 97% (n=32) and 100% (n=7), respectively. ORRs in patients with rituximab-refractory disease was 100% (n=14) and in patients with POD24 disease was 100% (n=11). With a median follow-up of 11.2 months, median PFS and median DOR were not reached and appeared to be similar, regardless of rituximab-refractory, POD24, or EZH2 mutation status. Conclusions: TAZ + R2 combination therapy demonstrates a consistent and manageable safety profile, with no new safety signals. The combination therapy maintained its efficacy, regardless of mutation status. Durable responses were seen in patients with high-risk disease, including those with rituximab-refractory and POD24 disease. The 2-arm randomized phase 3 portion will further explore the efficacy and safety of TAZ RP3D 800 mg + R2 in ≈500 patients with R/R FL who completed ≥1 prior systemic therapy.

AML-464 Tolerability and Efficacy of the First-In-Class Anti-CD47 Antibody Magrolimab Combined With Azacitidine in Frontline Patients With TP53-Mutated Acute Myeloid Leukemia (AML): Phase 1b Results

Patients with TP53-mutated AML have a poor prognosis. Magrolimab is an antibody blocking CD47, a "don't eat me" signal on cancer cells, which induces tumor phagocytosis and is synergistic with azacitidine. Report final tolerability and efficacy data. Ph1b single-arm trial of magrolimab+azacitidine (NCT03248479). 72 frontline patients with TP53-mutated AML unsuitable for intensive chemotherapy. Magrolimab IV 1-mg/kg (priming) then 30-mg/kg ramp-up QW/Q2W (maintenance). Azacitidine 75 mg/m2 IV/SC days 1-7 (each 28-day cycle). Primary endpoints were safety/tolerability and complete remission (CR) rate. Common treatment-emergent adverse events (TEAEs) were constipation (52.8%), diarrhea (47.2%), febrile neutropenia (45.8%), nausea (43.1%), fatigue (37.5%), decreased appetite (37.5%), thrombocytopenia (31.9%), peripheral edema (30.6%), and cough (30.6%). Common grade (G)≥3 TEAEs were febrile neutropenia (37.5%), anemia (29.2%; G3, 26.4%; G4, 2.8%), thrombocytopenia (29.2%), pneumonia (26.4%), and neutropenia (20.8%). G3 hemolysis was reported in 1 patient; no G4 hemolysis was reported. Objective response rate was 48.6% (CR, 33.3%; CR with incomplete hematologic recovery [CRi]/CR with partial hematologic recovery [CRh], 8.3%; morphologic leukemia-free state [MLFS], 1.4%; partial remission, 5.6%). 16.7% and 5.6% of patients had stable disease and progressive disease (PD), respectively; 30- and 60-day mortality rates were 8.3% and 18.1%, respectively. Response assessments were unavailable in 4.2% (discontinued due to AEs) and 6.9% (other) of patients prior to the C3D1 assessment. Median time to CR/CRi was 2.2 months (range, 1.7-7.2) and CR was 3.0 months (range, 1.8-9.6); 14/31 (45.2%) evaluable patients with CR/CRi/CRh/MLFS achieved negative MRD. 8/24 patients with CR had a longitudinal TP53 variant-allele-frequency (VAF) assessment; 5/8 (63%) had ≤5% VAF. Treatment was stopped due to stem cell transplant (9 [12.5%]), PD (26 [36.1%]), death (8 [11.1%]), AE (13 [18.1%]), or other (14 [19.4%]). Median durations of CR and CR/CRi were 7.7 (95% CI, 4.7-10.9) and 8.7 (95% CI, 5.3-10.9) months, respectively. Median overall survival was 10.8 months (95% CI, 6.8-12.8; 8.3-month median follow-up). Magrolimab+azacitidine showed durable responses and encouraging overall survival in frontline patients with TP53-mutated AML unsuitable for intensive chemotherapy. A Ph3 trial of magrolimab+azacitidine vs standard-of-care in TP53-mutated AML (ENHANCE-2; NCT04778397) is ongoing.

Adebrelimab (SHR-1316) in Combination With Chemotherapy as Perioperative Treatment in Patients With Resectable Stage II to III NSCLCs: An Open-Label, Multicenter, Phase 1b Trial

IntroductionThis study evaluated adebrelimab (a programmed death-ligand 1 antibody) plus nab-paclitaxel and carboplatin as perioperative treatment for resectable NSCLC. MethodsEligible patients had resectable stage II to III NSCLCs without driver gene. Patients received neoadjuvant treatment with three cycles of intravenous adebrelimab (20 mg/kg on day 1), nab-paclitaxel (100 mg/m2 on days 1, 8, and 15), and carboplatin (area under the curve 5 mg/mL per min on day 1), of each 21-day cycle before surgical resection, and followed by 16 cycles of adebrelimab (20 mg/kg on day 1 in 3 wk) adjuvant treatment. The primary end point was major pathologic response (MPR) per blinded independent pathologic review. ResultsA total of 37 patients were enrolled and received planned neoadjuvant therapy. There were 34 patients (91.9%) who underwent surgery. As of data cutoff on January 25, 2022, 19 of the 37 patients (51.4%, 95% confidence interval [CI]: 35.9–66.6) achieved MPR per blinded independent pathologic review and 11 patients (29.7%, 95% CI: 17.5–45.8) achieved pathologic complete response. Furthermore, 26 patients (70.3%, 95% CI: 54.2–82.5) had an objective response per Response Evaluation Criteria in Solid Tumors version 1.1. The 12-month event-free survival rate was 77.8% (95% CI: 54.1–90.3). In addition, 29 patients (78.4%) had grade greater than or equal to three treatment-related adverse events (AEs) and nine (24.3%) had treatment-related serious AEs. No treatment-related deaths occurred. Grade greater than or equal to three surgery-related AEs within 30 or 90 days after surgery were both reported in five patients (14.7%). ConclusionsAdebrelimab plus nab-paclitaxel and carboplatin as perioperative therapy led to a substantial proportion of MPR and high resectability, with manageable toxicities. On the basis of the phase 1b results, phase 3 trial was initiated.

Tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in frontline TP53m AML patients: Phase 1b results.

7020 Background: Magrolimab is a monoclonal antibody blocking CD47, a “don’t eat me” signal overexpressed on cancer cells such as acute myeloid leukemia (AML). This blockade induces phagocytosis of tumor cells and is synergistic with azacitidine (AZA) via upregulation of “eat me” signals. We report data from a Phase 1b trial of magrolimab+AZA in frontline TP53-mutant ( TP53m) AML. Methods: Patients (pts) with frontline AML not suitable for intensive chemotherapy received IV magrolimab starting with a priming dose (1 mg/kg) followed by ramp-up to 30 mg/kg QW or Q2W as maintenance dose. AZA 75 mg/m2 was given IV or SC on Days 1–7 of each 28-day cycle. Primary endpoints were safety/tolerability and complete remission (CR) rate by ELN 2017 criteria. Results: 72 TP53m AML pts were treated (Table). Common all-grade TEAEs were constipation (52.8%), diarrhea (47.2%), febrile neutropenia (45.8%), nausea (43.1%), fatigue (37.5%), decreased appetite (37.5%), thrombocytopenia (31.9%), peripheral edema (30.6%), and cough (30.6%). Most common Grade 3+ TEAEs were febrile neutropenia (37.5%), anemia (29.2%; Grade 3, 26.4%; Grade 4, 2.8%), thrombocytopenia (29.2%), pneumonia (26.4%), and neutropenia (20.8%). Objective response rate (ORR) by intent-to-treat was 48.6% (33.3% CR, 8.3% CR with incomplete hematologic recovery [CRi] / CR with partial hematologic recovery [CRh], 1.4% morphologic leukemia-free state [MLFS], 5.6% partial response). Stable disease was reported in 16.7%, progressive disease (PD) in 5.6%. 30- and 60-day mortalities were 8.3% and 18.1%, respectively. Response assessment was unavailable in 4.2% who discontinued due to AEs and 6.9% due to other, prior to the C3D1 assessment. Median time to CR/CRi was 2.2 months (mos; range 1.7–7.2) and to CR was 3.0 mos (range 1.8–9.6). 45.2% (14/31) of evaluable CR/CRi/CRh/MLFS pts achieved negative MRD by flow cytometry (investigator reported). Of 24 CR patients, 8 had a longitudinal TP53 VAF assessment, and 5/8 (63%) had VAF decreased to ≤5%. Treatment was stopped due to SCT in 9 pts (12.5%), PD 26 (36.1%), death 8 (11.1%), AE 13 (18.1%), and other 14 (19.4%). Median durations of CR and CR/CRi were 7.7 mos (95% CI: 4.7, 10.9) and 8.7 mos (95% CI: 5.3, 10.9), respectively. Median overall survival (OS) for the 72 pts was 10.8 mos (95% CI: 6.8, 12.8) with median follow up 8.3 mos. Conclusions: In high-risk frontline TP53m AML pts unsuitable for intensive chemotherapy, magrolimab+AZA showed durable responses and encouraging OS in a single-arm study. A Phase 3 trial in TP53m AML (ENHANCE-2; NCT04778397) of this combination vs standard of care is ongoing. Clinical trial information: NCT03248479. [Table: see text]

Phase 1b results of a multicenter, randomized phase 1b/2 study of gemcitabine and cisplatin +/- CPI-613 as first-line therapy for patients with advanced biliary tract cancer (BilT-04).

4094 Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis despite systemic chemotherapy. Gemcitabine (G) and cisplatin (C) is a standard first-line systemic therapy with a reported overall response rate (ORR) of 26% and median overall survival (OS) of 11.7 months (mo). CPI-613/Devimistat (D) is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and a-ketoglutarate dehydrogenase enzymes of the tricarboxylic (TCA) cycle, preferentially within the mitochondria of cancer cells augmenting chemotherapeutic cytotoxicity. Methods: An investigator-initiated, multi-institutional phase 1b/2 trial is underway across 10 sites in the US investigating the combination of G 1000 mg/m2, C 25 mg/m2 and D (dose levels: (-1) 500, (1) 1000, (2) 1500 and (3) 2000 mg/m2) (GCD) on days 1 and 8 every 21 days in pts with previously untreated advanced BTC. The primary objective of the phase 1b portion (n = 20 pts; TiTE-CRM methodology) was to determine the recommended phase 2 dose (RP2D). The primary objective of the ongoing phase 2 portion (n = 48-58 pts; 2:1 randomization with Bayesian control arm) is to determine the best ORR with an alternative hypothesis of 43% (null of 25%); with 80% power and one-sided alpha of 0.05. Secondary objectives include evaluation of progression-free survival (PFS), OS, and safety. Exploratory objectives include targeted exome/ transcriptomic analysis using tissue, and metabolomic analysis using plasma (pre-, on- and post-treatment). Results: 20 pts were enrolled on phase 1b; median age 65 years (range 43-75), ECOG PS 0/1 (9/11), male/female (11/9), Caucasian (85%), intrahepatic/hilar/distal cholangiocarcinoma and gallbladder (9/5/3/3), and metastatic/locally advanced stage (15/5). CPI-613 dose level assignments were 1 pt each for (-1) and (1), 2 pts on (2), and 16 pts on (3). Median follow-up was 9.4 mos and median number of cycles was 9. Only 1 pt had dose-limiting toxicity (grade 2 creatinine elevation). RP2D for CPI-613 was 2000 mg/m2. In phase 1b, ORR was 40% (7 PR, 1 CR). Median PFS not estimable (NE) but probability of PFS at 9 months was 68.1% [95% CI, 38.1%-85.8%]. Median OS is 16.3 months [95% CI, 9.1-NE]. One locally advanced pt was resected with pathologic CR. Conclusions: The combination of GCD was well tolerated and demonstrates encouraging efficacy with ORR, PFS and OS in phase 1b. The randomized phase 2 portion of the trial is open and accruing patients. Clinical trial information: NCT04203160.

84P SHR-1316 vs placebo in combination with chemotherapy as perioperative treatment in patients with resectable stage II-III NSCLC: A randomized, double-blind, multicenter, phase Ib/III trial

SHR-1316 is a humanized IgG4 monoclonal PD-L1 antibody which has shown promising antitumor activity in solid tumors. This phase 1b/3 trial evaluates the efficacy and safety of SHR-1316 plus chemotherapy vs placebo plus chemotherapy as perioperative treatment for resectable NSCLC. Here, we reported the results from the phase 1b study. Eligible patients were resectable stage II and III (IIIA and T3N2M0 IIIB) NSCLCs without EGFR/ALK alterations. Patients received neoadjuvant treatment with 3 cycles of intravenous SHR-1316 (20 mg/kg on day 1), nab-paclitaxel (100 mg/m2 on days 1, 8, and 15), and carboplatin (area under the curve 5, 5 mg/mL per min on day 1), of each 21-day cycle, followed by surgical resection. After that, patients further received 16 cycles of SHR-1316 (20 mg/kg on day 1) adjuvant treatment. The primary endpoint was major pathological response (MPR) per blinded independent pathological review (BIPR), defined as ≤10% viable tumor cells in resection specimen. If MPR was >55% then phase 3 trial will be initiated. From Jul 14, 2020 to May 12, 2021, 37 patients received SHR-1316 plus chemotherapy neoadjuvant treatment and 34 patients underwent surgery. As of data cutoff on Nov 26, 2021, 19 (55.9%, 95% CI 39.5-71.1) of the 34 patients underwent surgery achieved MPR per BIPR and 11 (32.4%, 95% CI 19.1-49.2) patients achieved pathological complete response. Of the 37 patients received neoadjuvant treatment, 26 (70.3%, 95% CI 54.2-82.5) patients had an objective response per RECIST v1.1, including 1 with complete response and 25 with partial response. Treatment-related adverse events (AEs) were reported in 37 (100%) patients. 29 (78.4%) patients had grade ≥3 treatment-related AEs and 9 (24.3%) had treatment-related serious AEs. No treatment-related deaths occurred. Grade ≥3 surgery-related AEs within 30 or 90 days after surgery were both reported in 6 (17.6%) of the 34 patients. SHR-1316 in combination with nab-paclitaxel and carboplatin as neoadjuvant therapy showed a high proportion of MPR in resectable NSCLC, and the safety profile was well tolerated. Based on the phase 1b results, the phase 3 trial was initiated and ongoing.

Venetoclax Combined with FLAG-IDA Induction and Consolidation in Newly Diagnosed Acute Myeloid Leukemia

Venetoclax Combined with FLAG-IDA Induction and Consolidation in Newly Diagnosed Acute Myeloid Leukemia

AML-204: Venetoclax Combined with FLAG-IDA Induction and Consolidation in Newly Diagnosed Acute Myeloid Leukemia

Context: FLAG-IDA induction results in complete remission in approximately 85% of newly diagnosed patients with acute myeloid leukemia (ND-AML), however 30-40% experience relapse. Combining the BCL-2 inhibitor venetoclax (VEN) with chemotherapy improves efficacy, inferring FLAG-IDA+VEN may improve outcomes in ND-AML. Objectives: The primary P2 objective was determination of the overall activity of FLAG-IDA+VEN. Key secondary objectives include overall response rate (ORR: CR+CRi+CRh+MLFS+PR), CRc (CR+ CRh+CRi), overall survival (OS), event-free survival (EFS), and duration of response (DOR). Design: A Phase 1b/2 study evaluating FLAG-IDA+VEN in ND and relapsed/refractory (R/R) AML patients ≥ 18 years of age. Phase 1b results were previously reported (DiNardo, JCO 2021). The Phase 2 (P2) portion enrolled patients into two cohorts: ND-AML (n=38), and R/R-AML (n=39). ND-AML outcomes are reported herein. Results: Thirty-eight patients with ND-AML (sAML: n=7, therapy-related AML: n=5) enrolled. Median age was 44 years (range 20-65). ELN risk was favorable, intermediate, and adverse in 18%, 37%, and 45% of patients. Three patients were too early for response evaluation. The ORR was 94% (CR: n=24 [69%], CRh: n=5 [14%], CRi: n=1 [3%], MLFS: n=3 [9%]) and corresponding CRc rate was 86% (n=30). 93% of CRc patients attained MRD-negative status. Patients received a median of 2 (range: 1-6) cycles. 57% (n=20) transitioned to allogeneic stem-cell transplant (HSCT). Median DOR was 18.4 (95% CI: 13.1-21.1) months. Median cycle length for cycles 1 and 2 were 31 and 41 days. No 30 or 60-day mortality occurred. Common adverse events included febrile neutropenia (34%), pneumonia (28%), cellulitis (16%), and bacteremia (16%). Eight patients relapsed (ELN intermediate: N=3, ELN adverse: N=5) including 100% of patients with baseline TP53 mutations (N= 4); and there have been 4 deaths, all in relapsed patients. Five relapses and three of four deaths occurred post-HSCT. After a median study follow up of 15 months, median EFS and OS were NR, with 1-year EFS and OS rates of 76% and 96%, respectively. Conclusions: FLAG-IDA+VEN induction and consolidation results in high MRD-negative composite CR rates in ND-AML with an expected safety profile. Durable responses were observed at 12-months. Long-term follow up is ongoing to confirm these results. FLAG-IDA induction results in complete remission in approximately 85% of newly diagnosed patients with acute myeloid leukemia (ND-AML), however 30-40% experience relapse. Combining the BCL-2 inhibitor venetoclax (VEN) with chemotherapy improves efficacy, inferring FLAG-IDA+VEN may improve outcomes in ND-AML. The primary P2 objective was determination of the overall activity of FLAG-IDA+VEN. Key secondary objectives include overall response rate (ORR: CR+CRi+CRh+MLFS+PR), CRc (CR+ CRh+CRi), overall survival (OS), event-free survival (EFS), and duration of response (DOR). A Phase 1b/2 study evaluating FLAG-IDA+VEN in ND and relapsed/refractory (R/R) AML patients ≥ 18 years of age. Phase 1b results were previously reported (DiNardo, JCO 2021). The Phase 2 (P2) portion enrolled patients into two cohorts: ND-AML (n=38), and R/R-AML (n=39). ND-AML outcomes are reported herein. Thirty-eight patients with ND-AML (sAML: n=7, therapy-related AML: n=5) enrolled. Median age was 44 years (range 20-65). ELN risk was favorable, intermediate, and adverse in 18%, 37%, and 45% of patients. Three patients were too early for response evaluation. The ORR was 94% (CR: n=24 [69%], CRh: n=5 [14%], CRi: n=1 [3%], MLFS: n=3 [9%]) and corresponding CRc rate was 86% (n=30). 93% of CRc patients attained MRD-negative status. Patients received a median of 2 (range: 1-6) cycles. 57% (n=20) transitioned to allogeneic stem-cell transplant (HSCT). Median DOR was 18.4 (95% CI: 13.1-21.1) months. Median cycle length for cycles 1 and 2 were 31 and 41 days. No 30 or 60-day mortality occurred. Common adverse events included febrile neutropenia (34%), pneumonia (28%), cellulitis (16%), and bacteremia (16%). Eight patients relapsed (ELN intermediate: N=3, ELN adverse: N=5) including 100% of patients with baseline TP53 mutations (N= 4); and there have been 4 deaths, all in relapsed patients. Five relapses and three of four deaths occurred post-HSCT. After a median study follow up of 15 months, median EFS and OS were NR, with 1-year EFS and OS rates of 76% and 96%, respectively. FLAG-IDA+VEN induction and consolidation results in high MRD-negative composite CR rates in ND-AML with an expected safety profile. Durable responses were observed at 12-months. Long-term follow up is ongoing to confirm these results.

Poster: MDS-158: Updated Safety and Efficacy of Venetoclax in Combination with Azacitidine for the Treatment of Patients with Treatment-Naïve, Higher-Risk Myelodysplastic Syndromes: Phase 1b Results

Poster: MDS-158: Updated Safety and Efficacy of Venetoclax in Combination with Azacitidine for the Treatment of Patients with Treatment-Naïve, Higher-Risk Myelodysplastic Syndromes: Phase 1b Results

Poster: AML-196: The First-in-Class Anti-CD47 Antibody Magrolimab in Combination with Azacitidine Is Well Tolerated and Effective in AML Patients: Phase 1b Results

Poster: AML-196: The First-in-Class Anti-CD47 Antibody Magrolimab in Combination with Azacitidine Is Well Tolerated and Effective in AML Patients: Phase 1b Results

AML-196: The First-in-Class Anti-CD47 Antibody Magrolimab in Combination with Azacitidine Is Well Tolerated and Effective in AML Patients: Phase 1b Results

Context: Magrolimab, an anti-CD47 antibody, induces tumor phagocytosis and eliminates leukemia stem cells. Azacitidine (AZA) synergizes with magrolimab by inducing prophagocytic “eat me” signals. Magrolimab + AZA is clinically effective in acute myeloid leukemia (AML) and myelodysplastic syndrome. Objective: To report Phase 1b data of magrolimab + AZA in untreated AML. Design: This is an open-label, nonrandomized, Phase 1b, interventional study. Interventions: Patients received a magrolimab priming/intrapatient dose-escalation regimen (1–30 mg/kg intravenous weekly followed by 30 mg/kg every 2 weeks in cycle 3 and beyond) and AZA (75 mg/m2 on days 1–7 on a 28-day cycle). Patients or Other Participants: Treatment-naive AML patients unfit for intensive chemotherapy. Main Outcomes Measures: Outcome measures included the percentage of patients with adverse events (AEs), objective response (OR), time to response, and duration of response. Results: Fifty-two patients were treated with magrolimab + AZA. Overall, 64% had poor-risk cytogenetics, and 65% had TP53 mutations. Magrolimab + AZA was well tolerated with a safety profile similar to AZA monotherapy. Treatment-related AEs (≥15% of patients) were anemia (31%), fatigue (19%), blood bilirubin increase (19%), neutropenia (19%), thrombocytopenia (17%), and nausea (15%). On-target anemia was generally transient and reversible, and no immune-related AEs associated with magrolimab were observed. Of 34 patients evaluable for efficacy, 22 (65%) achieved an OR, 15 (44%) achieved complete response (CR), 4 (12%) with CR with incomplete count recovery (CRi), 1 (3%) with partial response, 2 (6%) with morphological leukemia-free state (MLFS), 11 (32%) with stable disease (SD), and 1 (3%) with progressive disease (PD). Time to response was 2.04 months. In TP53-mutant patients, 15/21 (71%) achieved an OR, 10 (48%) achieved a CR, 4 (19%) with CRi, 1 (5%) with MLFS, 5 (24%) with SD, and 1 (5%) with PD. The median overall survival for TP53-mutant patients (n=34) and TP53–wild-type patients (n=16) was 12.9 and 18.9 months, respectively, with a median follow-up of 4 and 12 months, respectively. Conclusions: Magrolimab + AZA was well tolerated, with efficacy in both TP53-mutant and TP53–wild-type AML patients. A Phase 3 trial evaluating magrolimab + AZA in untreated TP53-mutant AML patients is planned (NCT04778397). Magrolimab, an anti-CD47 antibody, induces tumor phagocytosis and eliminates leukemia stem cells. Azacitidine (AZA) synergizes with magrolimab by inducing prophagocytic “eat me” signals. Magrolimab + AZA is clinically effective in acute myeloid leukemia (AML) and myelodysplastic syndrome. To report Phase 1b data of magrolimab + AZA in untreated AML. This is an open-label, nonrandomized, Phase 1b, interventional study. Patients received a magrolimab priming/intrapatient dose-escalation regimen (1–30 mg/kg intravenous weekly followed by 30 mg/kg every 2 weeks in cycle 3 and beyond) and AZA (75 mg/m2 on days 1–7 on a 28-day cycle). Treatment-naive AML patients unfit for intensive chemotherapy. Outcome measures included the percentage of patients with adverse events (AEs), objective response (OR), time to response, and duration of response. Fifty-two patients were treated with magrolimab + AZA. Overall, 64% had poor-risk cytogenetics, and 65% had TP53 mutations. Magrolimab + AZA was well tolerated with a safety profile similar to AZA monotherapy. Treatment-related AEs (≥15% of patients) were anemia (31%), fatigue (19%), blood bilirubin increase (19%), neutropenia (19%), thrombocytopenia (17%), and nausea (15%). On-target anemia was generally transient and reversible, and no immune-related AEs associated with magrolimab were observed. Of 34 patients evaluable for efficacy, 22 (65%) achieved an OR, 15 (44%) achieved complete response (CR), 4 (12%) with CR with incomplete count recovery (CRi), 1 (3%) with partial response, 2 (6%) with morphological leukemia-free state (MLFS), 11 (32%) with stable disease (SD), and 1 (3%) with progressive disease (PD). Time to response was 2.04 months. In TP53-mutant patients, 15/21 (71%) achieved an OR, 10 (48%) achieved a CR, 4 (19%) with CRi, 1 (5%) with MLFS, 5 (24%) with SD, and 1 (5%) with PD. The median overall survival for TP53-mutant patients (n=34) and TP53–wild-type patients (n=16) was 12.9 and 18.9 months, respectively, with a median follow-up of 4 and 12 months, respectively. Magrolimab + AZA was well tolerated, with efficacy in both TP53-mutant and TP53–wild-type AML patients. A Phase 3 trial evaluating magrolimab + AZA in untreated TP53-mutant AML patients is planned (NCT04778397).

MDS-158: Updated Safety and Efficacy of Venetoclax in Combination with Azacitidine for the Treatment of Patients with Treatment-Naïve, Higher-Risk Myelodysplastic Syndromes: Phase 1b Results

Background: Venetoclax (Ven), a selective oral BCL-2 inhibitor, demonstrated synergy with azacitidine (Aza) in patients with higher-risk myelodysplastic syndromes (HR-MDS). Objective: We report updated safety and efficacy in an ongoing phase 1b study (NCT02942290) evaluating Ven+Aza for treatment-naïve HR-MDS patients. Methods: Patients (≥18yrs) with International Prognostic Scoring System (IPSS) intermediate-2 or high-risk MDS, bone marrow (BM) blasts <20% at baseline, and ECOG≤2 performance status were enrolled. Aza 75 mg/m2 was administered on Days (d) 1–7 of each 28-d cycle. Initial Ven dose was 400 or 800 mg daily in 28-d cycles. Due to poor tolerance, the study was amended to examine several dose cohorts (100, 200, and 400 mg x 14-d each 28-d cycle). Main Outcomes Measures: Primary objectives were assessing Ven+Aza safety profile and establishing RP2D. Key secondary objectives included overall response rate (ORR) and overall survival (OS). Results: At data cutoff (Dec. 15, 2020), 78 patients received Ven+Aza (51 at RP2D 400 mg x 14 d), with median follow-up time of 23 mos. Median age was 70 yrs; 72% male; 90% had excess BM blasts (>5 to 10%, n=21; >10 to 20%, n=49). Grade 3/4 neutropenia (59%) or thrombocytopenia (33%) were present at baseline. All patients experienced ≥1 treatment-emergent adverse event (TEAE), the most common being neutropenia (83%), nausea (55%), and constipation (54%); 96% experienced grade 3/4 TEAEs, with neutropenia (82%), febrile neutropenia (49%), and thrombocytopenia (42%) being most common. Neutropenia (49%), including febrile neutropenia (45%), was the most common serious TEAE. The 30-d mortality rate after first dose was 1%. Intention-to-treat ORR was 80%, including complete remission (CR,40%) and marrow CR (mCR, 40%); 42% mCR had hematologic improvement; no partial remissions recorded. For 31 CR patients, median time to CR and median duration of response was 2.6 and 13.8 mos (95% CI 8.9,–), respectively. Post-baseline transfusion independence rate (defined as no transfusion ≥8 weeks), for patients transfusion-dependent for RBC and/or platelets at baseline, was 46.5%. Median OS was 28.2 mos (95% CI 17.7, –). Median OS for 31 patients achieving CR was 28.6 mos (95% CI 27.5, –). Twenty-three percent moved on to post-study allogeneic HSCT (including BM and peripheral blood stem cells). Conclusions: The combination of Ven+Aza was associated with rapid and durable response, promising efficacy, including remission rates and OS, and an acceptable safety profile for patients with HR-MDS. Additional correlation with disease risk features, including TP53 mutations, will be presented. Venetoclax (Ven), a selective oral BCL-2 inhibitor, demonstrated synergy with azacitidine (Aza) in patients with higher-risk myelodysplastic syndromes (HR-MDS). We report updated safety and efficacy in an ongoing phase 1b study (NCT02942290) evaluating Ven+Aza for treatment-naïve HR-MDS patients. Patients (≥18yrs) with International Prognostic Scoring System (IPSS) intermediate-2 or high-risk MDS, bone marrow (BM) blasts <20% at baseline, and ECOG≤2 performance status were enrolled. Aza 75 mg/m2 was administered on Days (d) 1–7 of each 28-d cycle. Initial Ven dose was 400 or 800 mg daily in 28-d cycles. Due to poor tolerance, the study was amended to examine several dose cohorts (100, 200, and 400 mg x 14-d each 28-d cycle). Primary objectives were assessing Ven+Aza safety profile and establishing RP2D. Key secondary objectives included overall response rate (ORR) and overall survival (OS). At data cutoff (Dec. 15, 2020), 78 patients received Ven+Aza (51 at RP2D 400 mg x 14 d), with median follow-up time of 23 mos. Median age was 70 yrs; 72% male; 90% had excess BM blasts (>5 to 10%, n=21; >10 to 20%, n=49). Grade 3/4 neutropenia (59%) or thrombocytopenia (33%) were present at baseline. All patients experienced ≥1 treatment-emergent adverse event (TEAE), the most common being neutropenia (83%), nausea (55%), and constipation (54%); 96% experienced grade 3/4 TEAEs, with neutropenia (82%), febrile neutropenia (49%), and thrombocytopenia (42%) being most common. Neutropenia (49%), including febrile neutropenia (45%), was the most common serious TEAE. The 30-d mortality rate after first dose was 1%. Intention-to-treat ORR was 80%, including complete remission (CR,40%) and marrow CR (mCR, 40%); 42% mCR had hematologic improvement; no partial remissions recorded. For 31 CR patients, median time to CR and median duration of response was 2.6 and 13.8 mos (95% CI 8.9,–), respectively. Post-baseline transfusion independence rate (defined as no transfusion ≥8 weeks), for patients transfusion-dependent for RBC and/or platelets at baseline, was 46.5%. Median OS was 28.2 mos (95% CI 17.7, –). Median OS for 31 patients achieving CR was 28.6 mos (95% CI 27.5, –). Twenty-three percent moved on to post-study allogeneic HSCT (including BM and peripheral blood stem cells). The combination of Ven+Aza was associated with rapid and durable response, promising efficacy, including remission rates and OS, and an acceptable safety profile for patients with HR-MDS. Additional correlation with disease risk features, including TP53 mutations, will be presented.

Phase 1b Results of a Study to Assess the Efficacy and Safety of Vismodegib in Combination with Ruxolitinib in Patients with Intermediate- or High-Risk Myelofibrosis

Background: The JAK inhibitor (JAKi) ruxolitinib is approved for treatment of myelofibrosis (MF). Treatment for 5 years or more may be necessary to improve or stabilize bone marrow fibrosis, and a fraction of patients do not respond to ruxolitinib. The Hedgehog signaling pathway is involved in primitive and definitive bone marrow hematopoiesis, and maintenance of hematopoietic precursors, suggesting that addition of a Hedgehog pathway inhibitor (HPI) to ruxolitinib might improve responses. In a murine model of MF, a combination of a JAKi and HPI reduced fibrosis in the bone marrow and spleen and decreased splenomegaly. Vismodegib is a HPI approved for treatment of locally advanced and metastatic basal cell carcinoma. The MYLIE study aimed to assess the safety and efficacy of combined ruxolitinib and vismodegib for the treatment of MF. The pharmacokinetics (PK) of vismodegib were characterized in patients with intermediate or high-risk MF.Methods: In this phase 1b study, 10 patients with intermediate- or high-risk MF (per Dynamic International Prognostic Scoring System) received open-label vismodegib (150 mg/day orally) and ruxolitinib (15 or 20 mg orally twice daily, depending on baseline platelet count) for up to 48 weeks, or until withdrawal or discontinuation. PK samples were collected throughout the study. PK sampling was designed to characterize the PK of total and unbound vismodegib in this study for comparison with PK data collected in other patient populations. Efficacy outcomes assessed for phase 1b included spleen response (≥35% reduction in volume by computed tomography or magnetic resonance imaging) per central and investigator assessment, improvement in bone marrow fibrosis per central and investigator assessment (using European consensus grading system), symptom response (≥50% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score [MPN-SAF TSS]) and anemia response (per International Working Group for Myeloproliferative Neoplasms Research and Treatment [IWG-MRT] revised response criteria). We report results from the planned analysis of the phase 1b study for efficacy and safety at week 24.Results: Six patients with primary MF, 1 with post-polycythemia vera MF and 3 with post-essential thrombocythemia MF were treated with vismodegib and ruxolitinib for a median of 294.0 days. As of the interim analysis data cutoff (March 29, 2017), 4 patients had completed 48 weeks of study treatment with ruxolitinib and vismodegib, 5 patients were still receiving treatment, and 1 had discontinued treatment because of a vismodegib-related adverse event (AE) (dysgeusia). The most common AEs were muscle spasm (100% of patients), dysgeusia (50%), alopecia (50%), thrombocytopenia (50%), and nausea (40%). All were grade 1/2, except for 2 instances of grade 3 thrombocytopenia in 2 patients. Three patients experienced serious AEs: infection (3 patients), lung infiltration (1 patient), and vomiting (1 patient); none were considered by the investigators to be related to vismodegib. Because of AEs, 7 patients modified or interrupted their ruxolitinib dose, and 4 patients interrupted their vismodegib dose. At week 24, three patients achieved a ≥35% reduction in spleen volume (including the patient who discontinued early because the assessment occurred within the week 24 visit window) by central review (a spleen response occurred in 1 patient per the investigator assessment). According to the central reviews, no patients had improvement in bone marrow fibrosis (1 patient had improvement in bone marrow fibrosis per investigator assessment). Five patients experienced symptom response, and no patients experienced an anemia response. A further central review of bone marrow biopsy specimens from 5 patients at week 48 continued to show no improvement in fibrosis.Conclusions: There was no clear benefit of the addition of vismodegib to ruxolitinib in any of the phase 1b efficacy outcome measures assessed. Given the lack of evidence of a disease-modifying effect with addition of vismodegib to ruxolitinib, further evaluation of this combination will not be pursued.Source of funding: F. Hoffmann-La Roche DisclosuresKoschmieder:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Roche: Other: Clinical Trial participation; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Verstovsek:Incyte: Research Funding; NS Pharma: Research Funding; Blueprint Medicines Corp: Research Funding; Blueprint Medicines Corp: Research Funding; Galena BioPharma: Research Funding; Celgene: Research Funding; NS Pharma: Research Funding; Seattle Genetics: Research Funding; Genentech: Research Funding; Lilly Oncology: Research Funding; CTI BioPharma Corp: Research Funding; Astrazeneca: Research Funding; Promedior: Research Funding; Pfizer: Research Funding; Astrazeneca: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Celgene: Research Funding; CTI BioPharma Corp: Research Funding; Galena BioPharma: Research Funding; Roche: Research Funding; Pfizer: Research Funding; Lilly Oncology: Research Funding; Roche: Research Funding. Hooper:Roche Products Ltd: Employment. Tandon:F. Hoffmann-La Roche: Employment. Dimier:F. Hoffmann-La Roche: Employment, Other: Stock.

ARC-6: A phase 1b/2, open-label, randomized platform study to evaluate efficacy and safety of etrumadenant (AB928)-based treatment combinations in patients with metastatic castrate-resistant prostate cancer (mCRPC).

5039 Background: Standard-of-care (SOC) chemotherapy may contribute to immunosuppression by elevating intratumoral levels of adenosine, activating the A2a and A2b receptors on immune cells. Extracellular adenosine is primarily produced by the enzyme CD73; in prostate cancer, additional adenosine is also produced by the highly expressed protein, prostatic acid phosphatase (PAP). Etrumadenant (etruma) is an orally bioavailable, small-molecule, selective dual adenosine receptor antagonist and has been well tolerated in dose escalation studies as monotherapy or combined with chemo/immunotherapy. Adenosine axis inhibition combined with SOC regimens and/or immunotherapy may have a synergistic effect on the induction of sustained antitumor immunity against mCRPC. Initial results from the etruma + zimberelimab (zim; anti–PD-1 mAb) + docetaxel (doc) arm are presented herein. Methods: ARC-6 (NCT04381832) is an ongoing, phase 1b/2, open-label, multicohort platform study to evaluate efficacy and safety of etruma combination therapy. All eligible patients (pts) have mCRPC that has progressed on androgen deprivation therapy and are checkpoint inhibitor-naive; additionally, for this arm, pts must be androgen signaling inhibitor (ASI)-experienced and taxane-naive. Study pts receive 150 mg etruma orally once daily + 360 mg zim IV every 3 weeks + SOC doc (EZD). The primary objectives are to evaluate safety and antitumor activity (prostate-specific antigen [PSA], radiographic, and composite response rates) of EZD. PSA levels are assessed every 3 weeks, and radiographic scans are performed every 12 weeks. PSA response-evaluable pts have baseline (BL) + ≥2 consecutive post-BL PSA assessments; radiographic response-evaluable pts have RECIST measurable or non-measurable disease per BL imaging + ≥1 post-BL radiographic assessment. Results: As of 22Jan2021, 17 pts have received EZD in phase 1b; 14 are PSA response-evaluable and 8 are radiographic response-evaluable. 15 (88%) pts reported treatment emergent adverse events (TEAEs); the most common ( &gt; 30%) were lymphocyte count decreased and neutrophil count decreased (7 pts each; 41%), and hyponatremia and alopecia (6 pts each; 35%). Grade ≥3 treatment-related TEAEs were reported by 9 pts (53%). As of 22Jan2021, 16 pts were continuing treatment; median time on EZD for all pts was 9.9 weeks (0.1–27.4+ weeks). In response-evaluable pts, PSA response rate was 36% (5/14), radiographic response rate was 38% (3/8; 1 CR), and the composite response rate was 43% (6/14). Conclusions: Phase 1b results indicate that EZD treatment in pts with mCRPC had a manageable safety profile and was associated with clinical benefit. Having met phase 2 advancement criteria, randomized pt enrollment to EZD vs. doc is ongoing. Clinical trial information: NCT04381832.

Phase Ib trial of varlitinib plus weekly paclitaxel in EGFR/HER2 co-expressing advanced gastric cancer (AGC).

227 Background: EGFR and HER2 are over-expressed in gastric cancer, and activation of EGFR signaling in HER2-overexpressing gastric cancer can confer resistance to HER2-directed treatment like trastuzumab. Varlitinib (also known as ASLAN001) is a small-molecule, adenosine triphosphate competitive inhibitor of the tyrosine kinases - EGFR, HER2, and HER4. We present phase 1b results of the phase1b/2 study to evaluate the safety and efficacy of varlitinib in combination with weekly paclitaxel in EGFR/HER2 co-expressing AGC patients as a second-line treatment. (KCT0003583). Methods: An open-label phase Ib trial was conducted using a 3+3 design. AGC patients who had failed first-line fluoropyrimidine-containing chemotherapy, with evidence of both EGFR and HER2 overexpression by IHC (≥1+), were enrolled. The primary objective was to assess the dose limiting toxicity (DLT) and recommended phase 2 dose (RP2D) of varlitinib [Dose 1: 300 mg BID, Dose -1: 300mg intermittent dose] and weekly paclitaxel (80 mg/m2 D1,8,15) every 4 weeks along with evaluation of anti-tumor activity. Results: From July 2019 to May 2020, 9 patients were enrolled at Dose 1 level of varlitinib 300mg bid and 6 patients were evaluable for safety per protocol. Two patients did not finish DLT period: one patient withdrew after 1 week and one patient received palliative surgery for panperitonitis caused by gastric cancer metastasis. One patient had major violation in IP administration as the patient took varlitinib intermittently. Among the 6 evaluable patients, there was 1 DLT of G4 AST/ALT elevation and G3 hyperbilirubinemia, which resolved after 3 weeks. The most common treatment related adverse events (TRAEs) were neutropenia (n=5), all of which were grade ≥ 3, but no lasting more than 7 days. Grade 2 TRAEs included rash (n=2), mucositis (n=2) and peripheral sensory neuropathy (n=2). After a median follow-up of 3.0 (range, 1.9~ 6.2) months, the best responses were stable disease in 4 patients. Currently, 4 patients are ongoing. Conclusions: The combination of varlitinib 300mg bid and weekly paclitaxel 80mg showed manageable safety profiles and determined as RP2D. Currently, multi-site phase 2 part is now underway. Clinical trial information: KCT0003583.