Dose-finding Cohort Research Articles

Phase I Trial of Brentuximab Vedotin Plus Cyclosporine in Relapsed/Refractory Hodgkin Lymphoma

IntroductionBV is an antibody-drug conjugate directed against CD30 and is safe and effective in relapsed/refractory (R/R) Hodgkin lymphoma (HL). Most patients with r/r cHL respond well to BV monotherapy; however, the large of majority of them eventually progress on this drug, and BV-resistant HL remains an unmet need. Preclinical data suggest that BV resistance is mediated at least in part by increased drug efflux associated with increased expression of multidrug resistance pump 1 (MDR1) while CD30 expression appears to be preserved in BV resistant cell lines and patient samples. We conducted a phase 1 study evaluating BV + cyclosporine (CsA) in BV-refractory HL and previous reported results in the dose finding cohort. Here we report the final results from the phase 1 study. MethodsThis was a phase I trial of BV + CsA in patients with r/r HL with dose-finding and dose escalation cohorts. Eligibility criteria included age ≥ 18 years with r/r HL after at least 1 prior line of therapy. Treatment consisted of 1.8 mg/kg BV intravenously on day 1 and CsA 5 to 7.5 mg/kg PO twice daily on days 1 to 5; cycles were 21 days long. Patients in the expansion cohort had to have cHL refractory to BV. The primary objectives were to evaluate safety and tolerability and to determine MTD of BV + CsA; the secondary objective was to determine efficacy of this combination. Results29 patients were enrolled onto the study, 14 in the dose finding cohort and 15 in the dose expansion BV refractory cohort. Study accrual was terminated before target accrual due to unacceptable toxicity. 62% of patients were male, and the median age was 36 years (range: 20-69). The median number of prior therapies was 5 (range: 3-12); all patients had prior BV, and 93% had PD-1 directed therapy, and 93% were BV-refractory. Of 22 evaluable patients, CR rate was 27% and ORR 64%; median DOR 4.9 months. Treatment-related deaths occurred in 3 patients, and another patient died during cycle 1 due to cardiac arrest deemed unlikely related to be protocol therapy. All grade GI toxicity was seen in 90% of patients (G3+ in 24%); other common adverse events were nausea (90%), hypertension (90%), nausea (90%), hypertension (90%), anemia (86%), fatigue (76%), neutropenia (76%), leukopenia (76%), hypomagnesemia (76%), anorexia (66%), and hyponatremia (66%). DiscussionBV + CsA demonstrated modest activity in BV-refractory r/r HL; however, toxicity is substantial.

Phase Ia/Ib trial on the safety and efficacy of mobocertinib in combination with T-DM1 for patients with HER2-mutant solid tumors (WJOG16022M).

3025 Background: Safety and efficacy of HER2 tyrosine kinase inhibitor (TKI) and anti-HER2 antibody-drug conjugate (ADC) in HER2-mutant solid tumors have not been investigated. Methods: Mobocertinib, a potent HER2 TKI plus T-DM1, an anti-HER2 ADC was evaluated in this phase I study. In a dose-finding cohort (phase Ia, pIa), the maximum tolerated dose was estimated in patients (pts) irrespective of HER2 mutational status. To further establish safety and evaluate preliminary efficacy, additional pts with HER2 mutations were enrolled in a dose-expansion cohort (phase Ib, pIb). Mobocertinib of 80, 120 to 160 mg was orally administered with intravenous T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint was to determine the recommended dose (RD) (pIa), and to evaluate the confirmed objective response rate (ORR) (pIb). Results: Between Nov 2022 and Jun 2023, a total of 28 pts, 6 in the pIa and 22 in the pIb were enrolled to this study (14 NSCLC; 4 cervical; 2 duodenal papilla; 2 pancreatic, median follow-up, 6.4 mo [range, 1.9 to 12.9 mo]). The median age was 54 (range, 40-84) years, 17 pts were female. Among 27 pts with HER2-mutant tumors, mutations in kinase domain were most common (66.7%). In the pIa cohort, 3 DLTs were observed with mobocertinib 120 mg, including grade 3 thrombocytopenia, grade 4 acute kidney injury, and drug withdrawal due to nausea and anorexia, while there was no DLT with 80 mg. The RD was therefore determined to be mobocertinib 80 mg plus T-DM1 3.6 mg/kg. Among 22 pts in the pIb, grade ≥ 3 AE occurred in 72.7% of pts; the common events (>5%) being thrombocytopenia (50.0%), diarrhea (13.6%), and anorexia (13.6%). No interstitial lung disease/pneumonitis was observed. The ORR was 28.6%, the disease control rate (DCR) was 71.4%, and median progression-free survival (mPFS) was 3.2 mo (95% CI 1.6, 6.1) in the pIb. In 27 pts with HER2 mutations across all cohorts, the ORR was 42.3%, the DCR was 76.9%, and mPFS was 4.3 mo (95% CI 2.7, 6.7). Additionally, in 13 pts with HER2-mutant NSCLC including those who had developed resistance to trastuzumab deruxtecan, the ORR was 53.8%, the DCR was 84.6%, and mPFS was 6.1 mo (95% CI 2.9, 6.3). Conclusions: The RD of this study treatment is mobocertinib 80 mg plus T-DM1 3.6 mg. Combination therapy of HER2 TKI and HER2 ADC demonstrated feasibility and potential efficacy for HER2-mutant solid tumors. Clinical trial information: 2051220070 .

Phase I Study of Response-Adapted Treatment with Venetoclax, Obinutuzumab, and Magrolimab (VENOM) in Relapsed and Refractory Indolent B-Cell Malignancies

Background and Significance Targeted agents and immunotherapy have changed the treatment landscape for follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and chronic lymphocytic leukemia (CLL), but indefinite therapy leads to cumulative toxicity and excessive cost. CD47 is a checkpoint for the innate immune system providing an inhibitory signal to phagocytic macrophages and a rational therapeutic target in B-cell lymphoma. Magrolimab is a fully humanized IgG4 anti-human CD47 antibody, with high activity in FL when combined with rituximab (Advani NEJM 2018). Our objective is to test the safety of adding escalating doses of venetoclax to magrolimab and obinutuzumab in a response-adapted study design with planned dose expansion cohorts (www.clinicaltrials.govidentifier NCT04599634). Study Design and Methods Patients with grade 1-3A FL, MCL, MZL, or CLL relapsed after and/or refractory to ≥2 prior lines of therapy are eligible. Pts with FL are eligible after 1 prior therapy if FLIPI ≥2 or disease progression within 24 months of the end of the last therapy. Pts with MCL are eligible after 1 prior therapy if blastoid histology, 17p deletion, TP53 mutation, Ki67 ≥30%, or received Bruton's tyrosine kinase inhibitor (BTKi) as first-line therapy. Pts with CLL are eligible after 1 prior therapy if 17p deletion, TP53 mutation, or received both a BTKi and a BCL2 inhibitor. Eligibility includes age ≥18 and adequate organ function unless dysfunction secondary to lymphoma. A positive direct antiglobulin test without hemolytic anemia is allowed. Patients with a history of hemolytic anemia or autoimmune thrombocytopenia within 3 months of enrollment are excluded. No washout period is required for prior anti-lymphoma treatment. Active HIV, CMV, and hepatitis B or C are excluded. The safety of venetoclax, obinutuzumab, and magrolimab will first be determined in 2 dose-finding cohorts of up to 24 pts (Cohort 1: 6-12 pts with FL and Cohort 2: 6-12 pts with MZL, MCL, or CLL). During dose-finding, all pts start triplet therapy with venetoclax, obinutuzumab, and magrolimab (Figure 1). Magrolimab IV is administered at a 1mg/kg priming dose on D1 of the first cycle, followed by 30mg/kg x 3 weekly loading doses, then 30 mg/kg on D1 of each 4-wk cycle. Obinutuzumab IV is administered at 100mg on D1, 900mg on D2, and 1000mg on D8 and D15 of the first cycle, followed by 1000mg on D1 of each 4-wk cycle. Pts with FL receive venetoclax 800mg (DL1) daily throughout therapy duration, whereas pts with MZL, MCL, and CLL start venetoclax at 20mg with weekly escalation to 400mg (DL1) over 5 weeks. Dose-limiting toxicity is assessed during the first 4 wks for FL, and the first 5 wks for MZL, MCL, and CLL. If ≥2 of 6 pts in either arm experience DLT, 6 additional pts will be enrolled to the respective arm at DL(-1) of venetoclax (600mg for FL and 200mg for MZL, MCL, and CLL). After dose-finding is completed, expansion cohorts of each histology will first receive magrolimab and obinutuzumab for two 4-wk cycles in a window for translational research. On-treatment tumor biopsies are optional during the window. After the window, venetoclax will be added at the dose determined during dose-finding. FDG-PET and CT scans are performed at baseline, after window, and after cycles 3 and 6 of triplet therapy. During both dose-finding and dose-escalation, pts with complete response (CR) after 6 cycles of triplet therapy will stop therapy. If these pts relapse, they can be retreated with an additional 6 cycles of triplet therapy. Pts with partial response (PR) after 6 cycles of triplet therapy receive an additional 6 cycles of triplet therapy. All pts stop treatment after 12 cycles. The primary objective is safety, with secondary endpoints of overall response rate, duration of response, and PFS. Exploratory objectives include the identification of a molecular signature that predicts response to magrolimab and obinutuzumab, and correlation of response with circulating tumor DNA levels.

The Combination of Nivolumab and CC-486 Is Active in Hodgkin Lymphoma Refractory to PD-1 Blockade

Introduction: PD1 blockade is highly active in patients (pts) with relapsed/refractory (RR) Hodgkin lymphoma (HL); however, most patients ultimately progress on therapy, and HL that is refractory to PD1 blockade remains an unmet need. Furthermore, as PD-1 directed therapies are being administered in earlier lines, it is anticipated that pts with RR HL will be increasingly refractory to PD-1 directed therapies. Hypomethylating agents (HMA) have been shown to increase T-cell infiltration and upregulate PD-1 and CTLA-4 expression in tumors, as well as suppress myeloid-derived suppressor cells. We hypothesized that HMA might restore the sentivity of HL to PD-1 directed therapies. Therefore, we conducted a phase I study evaluating the safety and efficacy of nivolumab and CC-486, an oral HMA, in pts with RR HL refractory to PD-1 blockade. Methods:Adult pts with RR HL who had progressed after at least 1 prior line of therapy and were refractory to PD-1 therapy were enrolled to receive oral CC-486 and nivolumab IV in 28-day cycles. PD-1 refractoriness was defined as progressive disease (PD) as best response, or PD while receiving or within 12 weeks of the last anti-PD-1 directed therapy. Pts were treated in a dose-finding cohort at 2 dose levels (DL) using a Rolling 6 design and then in a dose expansion cohort at the recommended phase 2 dose (RP2D). In DL1, CC-486 was administered at 200 mg PO daily on days 1-7, and in DL2 CC-486 was dosed at 300 mg PO daily on days 1-7; nivolumab 480 mg IV was given on day 8 in both DLs. Treatment could be continued for up to 2 years. Primary endpoints were determination of the RP2D and overall response rate (ORR) defined as the proportion of patients with a complete response (CR) or partial response (PR). Responses were assessed by investigators using PET-CT according to the 2014 Lugano Classification. Results: As of July 7, 2023, 21 pts have been enrolled including 3 at DL1 and 18 at DL2 (RP2D). At baseline, 57% were male with a median age of 40 years (range 25-71), 95% had stage III-IV disease, and 71% had primary refractory disease, defined as lack of a complete remission (CR) or relapse within 3 months of frontline treatment. The median number of prior therapies was 6 (range 2-14), and 90% had prior brentuximab vedotin (BV). 76% of pts had received pembrolizumab, 67% had received nivolumab, and 43% had received both agents previously. 52% had undergone autologous stem cell transplant and 5% had had prior allogeneic stem cell transplant. Baseline characteristics are shown in Table 1. The median number of cycles was 7 (range: 3-17). Among 19 pts evaluable for response (2 pending), ORR was 63% and CR rate was 10%. An additional 32% had SD as their best response; only one pt had PD as the best response. The median follow-up time was 9 months (range 2.8-16.3), and 71% of pts remain on treatment with an estimated median PFS of 11.3 months (95% CI: 7.1-N/A). 6 pts stopped therapy, including 4 for disease progression, 1 at treating physician's discretion and 1 due to patient preference. The most common adverse events (AEs), any grade (Gr), were nausea (86%), diarrhea (71%), vomiting (48%), headache (33%), fatigue (29%), neutropenia (19%), and anemia (19%). Only two Gr 3+ AEs were recorded: one patient experienced Gr 3 anemia and another Gr 4 hypercalcemia. Notably, the hypercalcemia fully resolved with supportive care and did not recur with subsequent cycles. The only immune-related AE was grade 1 hypophysitis in a single pt. Conclusions: Nivolumab combined with CC-486 is tolerable and elicits a high response rate in a PD-1 refractory cohort. At this time, the study has been amended to enroll 10 more patients at DL2 to provide a better estimation of the efficacy.

Phase I Safety and Preliminary Efficacy of Acalabrutinib, Venetoclax, and Obinutuzumab (AVO) in Patients with Relapsed/Refractory Mantle Cell Lymphoma

Introduction: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), even when treated with novel targeted agents, generally have only limited benefit (Rule et al., Leukemia 2018). The triple combination of the first-generation Bruton tyrosine kinase inhibitor (BTKi), ibrutinib, the BCL-2 inhibitor, venetoclax, and anti-CD20 monoclonal antibody, obinutuzumab has demonstrated preliminary safety and efficacy in R/R and treatment naïve (TN) MCL (Le Gouill et al., Blood 2021). We therefore hypothesized that given the favorable toxicity profile of the second-generation BTKi, acalabrutinib, when given in combination with venetoclax and obinutuzumab (AVO), would be effective and well tolerated in both R/R and TN MCL. Here, we report the results of the phase I dose-finding cohort of AVO in patients with R/R MCL. Methods: This is an investigator-initiated, multicenter, multi-cohort phase I/II trial (NCT04855695). The primary endpoints of the phase I portion are the recommended phase II dose (RP2D) and the safety and tolerability of AVO in R/R MCL. The study was designed to evaluate up to 2 dose levels of acalabrutinib, starting with the FDA-approved dose (100 mg po bid, dose level 0 [DL0]) followed by a lower dose (100 mg po daily, DL-1) if dose limiting toxicities (DLTs) occurred in > 1/6 patients in DL0 during the first 4 cycles. Patients were treated in 28-day cycles with acalabrutinib starting with cycle 1, followed by obinutuzumab in cycle 2 (100 mg IV on day 1, 900 mg IV on day 2, 1000 mg IV on days 8 and 15, and on day 1 of cycles 3-7), and venetoclax (weekly dose ramp-up starting in cycle 3 to a target dose of 400 mg daily). Acalabrutinib and venetoclax were continued indefinitely and obinutuzumab maintenance was given every 2 cycles starting with cycle 9 for 12 doses. Patients with progressive disease (PD) or who were unable to receive > 80% of the doses of acalabrutinib and venetoclax during the first 4 cycles were replaced. Key eligibility criteria included R/R MCL after at least one anti-CD20 mAb-based therapy, ECOG PS ≤ 2, and adequate hematologic and organ function. Key exclusion criteria were progression or relapse following prior BTKi or BCL-2 inhibitor and CNS involvement. CTCAE v5 and Lugano criteria were used to evaluate toxicity and efficacy, respectively. Results: As of July 26, 2023, 9 patients in DL0 were evaluable for response as 3 patients were replaced prior to reaching the DLT window. The median age was 67 (range 63-79). 78% were male. Median number of prior treatments was 1 (range 1-2). 33% relapsed after autologous stem cell transplant and 22% had primary refractory disease. All patients had advanced stage MCL, with stage IV disease in 89%. MIPI score was 22% high, 56% intermediate, and 22% low risk. Ki67 index ≥ 30% in 44% and ≥ 50% in 33%. 33% patients had complex karyotype, 22% TP53 mutation, 33% p53 IHC expression > 50%, and 33% blastoid variant. No DLTs were observed and DL0 was determined to be the RP2D. All 9 patients were evaluable for toxicity (Figure 1A). Hematologic toxicity included neutropenia (67%; 33% Gr 3), thrombocytopenia (56%; 22% Gr 3/4), and anemia (22%; all Gr 3). The most common toxicities were headache (77%; all Gr 1/2), bruising (67%; all Gr 1), diarrhea (44%; all Gr 1/2), and upper respiratory infection (22%; 11% Gr 3). There were no serious adverse events. There was no occurrence of febrile neutropenia, atrial fibrillation, bleeding, or laboratory or clinical tumor lysis syndrome. Median follow-up was 6 months (range 1-21). ORR was 78% (7/9) and CR rate was 67% (6/9) after 3 cycles of AVO. Both patients with TP53 mutation and 2/3 patients with blastoid variant achieved CR. Of the 3 patients replaced prior to the DLT window, 2 patients had PD and 1 patient was unable to receive > 80% of the acalabrutinib and venetoclax doses due to grade 4 thrombocytopenia, although achieved CR. 5 patients (56%) remain on treatment and in CR. 1 patient achieved PR after cycle 3 but progressed after cycle 7. Median overall and progression-free survival were not reached. Conclusions: AVO is safe and feasible in patients with R/R MCL with no DLTs observed. RP2D was determined at the full FDA approved dosage of all three drugs. Preliminary efficacy is encouraging in this high-risk R/R MCL population. The phase II TN transplant ineligible or TP53 mutated MCL cohort is now enrolling with minimal residual disease (MRD)-guided time-limited therapy (Figure 1B). The phase I R/R expansion cohort will also open to enrollment.

DIPG-54. UPDATED FINDINGS FROM THE PHASE IB STUDY OF UNESBULIN (PTC596) IN CHILDREN WITH NEWLY-DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND HIGH-GRADE GLIOMA (HGG): A REPORT FROM THE COLLABORATIVE NETWORK FOR NEURO-ONCOLOGY CLINICAL TRIALS (CONNECT)

Abstract BMI-1 represents a potential therapeutic target in pediatric HGG given its role in self-renewal and DNA-damage signaling, high expression levels in these tumors, and resultant proliferation blockade, mitotic abnormalities, and radiosensitization when modulated by unesebulin, a microtubule polymerization inhibitor. This phase Ib study sought to determine the recommended phase 2 dose (RP2D) and pharmacokinetic (PK) profiles of unesbulin administered concurrently with radiotherapy and as maintenance therapy in children with newly-diagnosed DIPG or HGG, as well as assess intratumoral PKs and target inhibition within a surgical cohort. As previously reported, the established RP2D from the dose-finding cohort (parts A [capsule] and C [tablet]), consisting of 27 patients (median age: 9 years; 18 with DIPG, 9 with HGG) is 200mg/m2 twice weekly. Eleven additional patients (5 with DIPG, 6 with HGG) have been enrolled in an expansion cohort (part D [tablet]), with no dose-modifying toxicities to date. Among 38 total patients, most common drug-related grade 3/4 adverse effects observed are neutropenia (49%), leukopenia (31%), and elevated ALT (18%). Pharmacokinetic profiles are comparable between capsule and tablet formulations, and corroborate adult data. Genomics correlatives are underway on 13 biopsy and 5 autopsy specimens (2 paired samples). Five patients (median age: 5 years; 4 with DIPG, 1 with HGG) have enrolled in the surgical cohort (part B [tablet]) at the RP2D. PK analyses performed on the first three samples confirm intratumoral unesbulin exposure. In summary, the RP2D of unesbulin at 200mg/m2 twice weekly concurrent with and post-radiotherapy is feasible and well-tolerated, with evidence of blood-brain barrier and tumor penetrance. Survival outcomes as well as ongoing analyses of intratumoral BMI-1 pathway inhibition in surgical cohort samples, plus comprehensive molecular profiling (focusing on BMI-1 and cell cycle signaling) of biopsy and autopsy specimens from the entire cohort, will be shared at time of presentation.

A phase I/II study to evaluate the safety, pharmacodynamics, and efficacy of entinostat in combination with atezolizumab and bevacizumab in patients with renal cell carcinoma.

4526 Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) limit the efficacy of immunotherapies. We have previously reported that histone deacetylase (HDAC) inhibitors have antitumor effects in combination with PD-1 inhibition by inhibiting the function of Tregs and MDSCs in preclinical models. We hypothesized that HDAC inhibition may enhance or resensitize patients (pts) with renal cell carcinoma (RCC) to immunotherapy. Thus, we conducted a Phase I/II clinical study with the HDAC inhibitor entinostat in combination with the immune check point inhibitor atezolizumab and the VEGF inhibitor bevacizumab in RCC pts, either treatment naïve or previously treated with immune checkpoint inhibitors. Methods: The primary objective was to evaluate the safety, tolerability, and efficacy of this combination strategy in a Phase I/II clinical trial. This clinical study was composed of a Dose Finding Phase (Phase I) and a two-stage Phase (Phase II) portion. Due to unforeseen circumstances, enrollment was halted during Stage I of the Phase II portion. In the Phase I dose finding cohorts, according to the 3+3 standard design, pts received oral entinostat at 1 mg (dose level or dl1), 3 mg (dl 2), or 5 mg (dl 3) every 7 days, continuously, with atezolizumab at a dose of 1,200 mg/kg mg IV every three weeks in combination with bevacizumab at a dose of 15 mg/kg IV every 3 weeks. Phase II patients were split into two distinct cohorts: Cohort A (no prior treatments with PD-1 or PD-L1 inhibitors) and Cohort B (at least one prior treatment with a PD-1 or PD-L1 inhibitor for metastatic disease). Pts treated at dl3 were included in the Phase II efficacy analyses. Results: 31 pts (18 and 13 pts during Phase I and II, respectively) were enrolled. Phase I was completed with the following DLTs: hypertension (3) in dl1, encephalopathy and hyponatremia (dl2), pneumonitis and pruritis (dl3). Dl3 was established as the recommended phase II dose. The most common treatment-related toxicities were thrombocytopenia, hypophosphatemia, proteinuria, diarrhea, fatigue, and neutropenia. A total of 21 grade≥3 events were observed. Nine pts achieved a partial response in Cohort A and one patient in Cohort B with an ORR 60% (CI 32.3-83.7) and 33.3% (28.2-56.4), respectively. According to Simon’s optimal two-stage design, the ORR met the Stage I primary objective. The median PFS was 13.7 months (CI 8.7-21.3) in Cohort A and 9.8 months (CI 1.3-NE) in Cohort B. We have collected blood samples to conduct several correlative studies on peripheral blood mononuclear cells. Conclusions: The preliminary results from this study suggest that the combination of entinostat and atezolizumab plus bevacizumab is relatively well tolerated and may be active in pts with ccRCC. Clinical trial information: NCT03024437 .

Eprenetapopt combined with venetoclax and azacitidine in TP53-mutated acute myeloid leukaemia: a phase 1, dose-finding and expansion study

TP53-mutated acute myeloid leukaemia is associated with poor outcomes. Eprenetapopt (APR-246) is a first-in-class, small-molecule p53 reactivator. We aimed to evaluate the combination of eprenetapopt and venetoclax with or without azacitidine in patients with TP53-mutated acute myeloid leukaemia. This phase 1, multicentre, open-label, dose-finding and cohort expansion study was done at eight academic research hospitals in the USA. Inclusion criteria were age of at least 18 years; at least one pathogenic TP53 mutation; treatment-naive acute myeloid leukaemia according to the 2016 WHO classification; an ECOG performance status of 0-2; and a life expectancy of at least 12 weeks. In dose-finding cohort 1 patients received previous therapy with hypomethylating agents for myelodysplastic syndromes. In dose-finding cohort 2, previous use of hypomethylating agents was not permitted. Treatment cycles were 28 days. Patients in cohort 1 received intravenous eprenetapopt 4·5 g/day on days 1-4 and oral venetoclax 400 mg/day on days 1-28; those in cohort 2 also received subcutaneous or intravenous azacitidine 75 mg/m2 on days 1-7. The expansion part of the study proceeded with patients enrolled as in cohort 2. Primary endpoints were safety in all cohorts (assessed in patients receiving at least one dose of assigned treatment) and complete response in the expansion cohort (assessed in patients who completed at least one treatment cycle and had at least one post-treatment clinical response assessment). The trial is registered with ClinicalTrials.gov, NCT04214860, and is complete. Between Jan 3, 2020, and July 22, 2021, 49 patients were enrolled across all cohorts. Six patients were initially enrolled into each of dose-finding cohorts 1 and 2; after no dose-limiting toxicities were observed, cohort 2 was expanded to enrol an additional 37 patients. The median age was 67 years (IQR 59-73). 24 (49%) of 49 patients were female and 25 (51%) male, and 40 (82%) were White. At data cutoff (Oct 1, 2021), the median length of follow-up was 9·5 months (IQR 6·1-11·5). No dose-limiting toxicities were recorded and the recommended phase 2 dose for eprenetapopt combinations was 4·5 g/day on days 1-4. Across all patients, adverse events of grade 3 or worse occurring in at least 20% of patients were febrile neutropenia (23 [47%] of 49 patients), thrombocytopenia (18 [37%] patients), leukopenia (12 [25%] patients), and anaemia (11 [22%] patients). Treatment-related serious adverse events occurred in 13 (27%) of 49 patients and there was one (2%) treatment-related death (sepsis). 25 (64%, 95% CI 47-79) of 39 patients had an overall response with eprenetapopt and venetoclax with azacytidine; 15 (38%, 23-55) had a complete response. Eprenetapopt and venetoclax with azacitidine had an acceptable safety profile and encouraging activity, supporting further frontline evaluation of this combination in the treatment of TP53-mutated acute myeloid leukaemia. Aprea Therapeutics.

Abstract OT1-02-02: A phase 1/2 study to evaluate the safety and efficacy of EP0062, an oral Selective Androgen Receptor Modulator (SARM), for the treatment of AR+/HER2-/ER+ advanced breast cancer

Abstract There is growing interest in targeting the androgen receptor (AR) in advanced/metastatic breast cancer. It has been recently demonstrated preclinically that AR activation, rather than AR suppression, exerts potent antitumor activity across a number of ER+/AR+ breast tumors, including those resistant to standard-of-care endocrine therapy and CDK4/6 inhibitors (Hickey et al, Nature Medicine 2021 27: 310-320). Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. EP0062 is an oral, non-steroidal, SARM currently being developed for the treatment of AR+/HER2-/ER+ advanced breast cancer. The efficacy and safety of EP0062 has previously been investigated in a Phase 1 clinical trial of AR+/HER2–/ER+ advanced breast cancer, and demonstrated that EP0062 has acceptable tolerability with evidence of clinical efficacy (LoRusso et al. Clinical Breast Cancer 2022 22;1 67-77). This new study is designed to further extend the evaluation of EP0062 as a potential therapy for AR+/HER2–/ER+ advanced breast cancer. The primary aim of the study is to assess tolerability and identify an optimal RP2D dose. The study will also explore the relationship between efficacy of EP0062 and AR expression, to establish a threshold for future patient selection, and undertake an initial evaluation of the safety and efficacy of EP0062 in combination with established standard of care therapies. The study will recruit up to 128 patients with AR+/HER2-/ER+ advanced breast cancer. Module A is a dose finding cohort to investigate safety, tolerability, PK and PD and to define the maximum tolerated dose (MTD) and/or Recommended Phase II Dose (RP2D). Dose finding will be based on a 3+3 design and is expected to recruit up to 32 patients. Once potential recommended doses are identified, approximately 60 evaluable patients will be randomised to two different dose cohorts in Module B in order to further optimise the RP2D dose, by further evaluation of safety and tolerability, as well as prospectively evaluate the relationship between efficacy and AR expression. In Module C, EP0062 will be combined with select standard of care targeted therapies in patients with relapsed AR+/HER2-/ER+ advanced breast cancer to confirm safety and explore efficacy. This will include approximately 36 patients across a number of single arm expansion cohorts. The key inclusion criteria are as follows: • Post-menopausal women, ≥18 years • ECOG performance status of 0 to 1 • Locally advanced or metastatic breast cancer • ER+, HER2- as per ASCO CAP guidelines • AR+, as defined as ≥ 10% AR nuclei staining by IHC • Endocrine-sensitive defined as greater than 3 years endocrine treatment prior to recurrence if recurrence occurred in the adjuvant setting, or ≥ 6 months treatment and response if recurrence occurred from primary treatment in the advanced setting • Relapsed, defined as clear and documented evidence of disease progression following ≥ 1 lines and ≤2 prior lines of previous endocrine therapy and ≤ 2 lines of chemotherapy in the advanced/metastatic setting • Measurable disease defined by RECIST version 1.1, or measurable bone-only disease EP0062 will be dosed to progression. Endpoints include incidence of DLTs during Cycle 1 of EP0062 treatment (28 days), MTD, RP2D (Module A), incidence and severity of AEs and SAEs, plasma PK parameters, Clinical Benefit Rate (complete response, partial response, or stable disease) at 24 weeks, ORR, duration of response, PFS, OS and quality of life. Clinic follow-up will be at 2 and 4 weeks, then every 4 weeks until disease progression. Recruitment is scheduled to initiate in Q4 2022. Citation Format: Elgene Lim, Erika Hamilton, Carlo Palmieri, Hendrik-Tobias Arkenau, Sue Brook, Geoff Fisher, Andrew Mazur. A phase 1/2 study to evaluate the safety and efficacy of EP0062, an oral Selective Androgen Receptor Modulator (SARM), for the treatment of AR+/HER2-/ER+ advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-02-02.

Phase 2 Study of Aficamten in Patients With Obstructive Hypertrophic Cardiomyopathy

BackgroundLeft ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients. ObjectivesThis study aims to evaluate the safety and efficacy of aficamten in patients with oHCM. MethodsPatients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout. ResultsFrom baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: −40 ± 27 mm Hg, and −43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (−36 ± 27 mm Hg and −53 ± 44 mm Hg, P = 0.001 and <0.0001 vs placebo, respectively). There were modest reductions in EF (−6% ± 7.5% and −12% ± 5.9%, P = 0.007 and P < 0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro–B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms. ConclusionsAficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM.

A Phase I Trial Assessing the Feasibility of Romidepsin Combined with Brentuximab Vedotin for Patients Requiring Systemic Therapy for Cutaneous T-Cell Lymphoma

Introduction: Although most patients (pts) with cutaneous T-cell lymphoma (CTCL) have an indolent course, outcomes for advanced stages (≥IIB) are suboptimal (Dummer R, et al. Nat Rev Dis Primers, 2021). A more aggressive approach of combination cytotoxic therapies in CTCL in the past has been shown to result in higher response rates, but sequential therapies have similar disease-free and overall survival and less toxicities (Kaye FS et al, NEJM, 1989). With the advent of several biological agents in CTCL with favorable toxicity profiles compared to cytotoxics, including the CD30-directed antibody-drug conjugate brentuximab vedotin (BV), and HDAC inhibitors (HDACi), rational novel combinatorial approaches may be beneficial as response rates for single agents remain modest. Evidence suggests that HDAC inhibition may upregulate CD30 expression (Hasanali ZS et al, Sci Transl Med, 2015), supporting the combination of the HDACi romidepsin (R) with BV in pts with CTCL. Methods: In this multicenter phase I trial of R+BV, pts age ≥18 with stage ≥IB CTCL, good organ function, ECOG PS≤2, <Grade (G) 2 neuropathy, who required systemic treatment were enrolled irrespective of CD30 expression. A traditional "3+3" design with 4 dose levels (DL -2, -1, 0, & 1) was used to define the maximum tolerated dose (MTD). Prior HDACi or BV use was allowed. Enrollment started at DL 0, with R given at 10mg/m2 on days (D) 1, 8 & 15, and BV at 1.2mg/kg (max. 120mg) on D1 & 15 of a 28 day cycle for ≤16 cycles. At DL 1, the R dose was 14mg/m2, with BV 1.2mg/kg, both on D1 & 15. Dosing in the de-escalation cohorts -1 and -2 was as follows: R 10mg/m2 & BV 1.2mg/kg D1 & 15 (DL-1) or R 10mg/m2 D1, 8 & 15 with BV 0.9mg/kg D1 &15 (DL-2). Once the MTD was established, 9 additional pts were enrolled in an expansion cohort. Response was measured using the Global Response Score (GRS; Olsen EA et al. JCO, 2011) using the mSWAT for skin assessment, and flow cytometry and CT imaging every 3 cycles for assessment of extracutaneous sites. There was a "run-in" phase of treatment with R alone given 14 days prior to D1 (D-14) with skin biopsies taken at baseline and prior to C1D1 to assess changes in CD30 expression. The trial was registered in clinicaltrials.gov (NCT02616965). Results: A total of 15 pts were enrolled (DL0: n=3; DL1: n=3; expansion cohort: n=9). No pts were enrolled in the de-escalation cohorts. No pt in the dose finding cohorts experienced a DLT, and DL1 was determined as the MTD. In the expansion cohort at DL1, 9 pts were enrolled, 1 of which experienced a DLT (G3 fatigue >72h) during cycle 1. Median age was 65 years (range 51-79); 83% (n=12) were male; median ECOG PS 1 (0-2); median prior lines of systemic therapy 2 (0-4), including 2 pts with prior HDACi, and 3 pts with prior BV exposure. All pts had Mycosis fungoides (MF) or Sezary syndrome (SS). Stage at enrollment was stage IB in 2 (13%), IIB in 7 (47%), IVA1 and IVB in 1 each (7% each) and IVA2 in 4 (27%). The most common treatment-related adverse events (AE) were nausea (67%), vomiting, constipation, diarrhea, fatigue, leukopenia, peripheral sensory neuropathy (33% each), gastro-esophageal reflux, dizziness, dysgeusia, transaminitis, headaches, and neutropenia (20% each; see Table 1). No pts experienced ≥G4 AE. The only G3 AEs observed were transaminitis, fatigue and fever (n=1 each), all resolved spontaneously. Response assessment at data cut off on 7/1/22 was available for 11 of 15 pts. The overall response rate (ORR) by GRS was 64% (7/11; 95%CI 35-92%; n=1 CR). Both pts with prior HDACi exposure, and 2 of 3 with prior BV exposure responded. The median change in mSWAT was a decrease of 57% from baseline (range -25 to -100%, Fig 1). At data-cut off, 1 pt remained on treatment, while 7 pts (47%) came off treatment due to progression, 2 (13%) each due to non-adherence related to COVID-19 concerns and toxicities (recurrent thrombophlebitis; fatigue), and 1 (7%) each due to patient preference, provider preference and completion of study treatment after 16 cycles. With a median follow up of 8 months (0.2-38), median progression-free survival was 5.5m, and median OS not reached (1y OS 81%). Conclusion: In this phase I study exploring the combination of R+BV, the regimen was well tolerated and efficacious in MF/SS including heavily pretreated pts with advanced disease and prior exposure to HDACi and BV. Correlative studies, including analysis of changes in CD30 expression after 1 dose of R, and association of response with CD30 expression, are pending. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 1 Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of Bcl-2 Inhibitor Bgb-11417 in Adult Patients with Mature B-Cell Malignancies: Preliminary Data

Background/Introduction: The efficacy of Bcl-2 inhibitors in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was established by the approval of agents such as venetoclax across all lines of therapy. However, adverse events (AEs) related to venetoclax and the development of BCL2 mutations leading to resistance may limit the utility of venetoclax in the clinic. Compared to venetoclax, BGB-11417 is a more potent (>10 fold in biochemical assays) and highly selective Bcl-2 inhibitor with the potential to achieve deeper target inhibition and clinical responses. Here, we report preliminary data from a phase 1 trial of BGB-11417 in patients with mature B-cell malignancies. Methods: BGB-11417-102 (NCT04883957) is a multicenter, phase 1, open-label, dose-finding study conducted in China. The primary objectives were to determine the safety, maximum tolerated dose (MTD) or maximum administered dose, and the recommended phase 2 dose (RP2D) of BGB-11417 monotherapy for the selected B-cell malignancy dose-finding cohorts. Patients with relapsed/refractory (R/R) B-cell malignancies received escalating doses of BGB-11417 monotherapy (80, 160, 320, or 640 mg once daily) with a weekly or daily ramp-up to the intended target dose. Dose-limiting toxicity for each dose cohort was evaluated by a Bayesian logistic regression model during dose ramp-up through day 21 at intended dose. AEs were reported per Common Terminology Criteria for AEs v5.0. Results: As of June 16, 2022, 41 patients were treated. Twenty-seven with R/R non-Hodgkin lymphoma (NHL; 13 diffuse large B-cell lymphoma, 7 follicular lymphoma, 4 marginal zone lymphoma, and 3 transformed NHL) received BGB-11417 ≤640 mg/d and 14 with R/R CLL/SLL received ≤320 mg/d. MTD has not yet been reached. The median values were as follows: age, 62 years (range 31-84); lines of prior systemic therapy, 2 (range 1-7); and follow-up, 5.7 months (range 0.7-9.5). A total of 19 patients (18 NHL and 1 CLL/SLL) discontinued the study treatment (14 progressive disease, 4 withdrawal by subject, and 1 investigator decision). At least 1 treatment-emergent AE (TEAE) was reported by 97.6% of patients and grade ≥3 AEs were reported by 51.2%. The most common TEAEs (reported in ≥10% of patients) across all dose levels are listed in the Table. Dose-limiting toxicity events were reported in 7.3% of patients (grade 3 febrile neutropenia and grade 3 platelet count decrease at 80 mg/d dose level each; grade 3 bone pain at 160 mg/d dose level). Serious TEAEs were reported in 9.8% of patients, and TEAEs leading to drug interruption were reported in 12.2%. No patients reported TEAEs leading to death or treatment discontinuation. Laboratory tumor lysis syndrome (TLS) events were reported in 4.9% of patients, and all were controlled without dose modification. No clinical TLS events were reported. Of the 31 patients available for tumor assessment (23 NHL and 8 CLL/SLL), 4 patients with NHL and 5 patients with CLL/SLL achieved responses (NHL: 3 partial responses [PR] at 160 mg/d dose level and 1 PR at 320 mg/d dose level; CLL/SLL: 2 complete responses [CRs]/CR with incomplete count recovery, 1 PR at 80 mg/d dose level, and 2 PR at 160 mg/d dose level). One patient with CLL had a CLL count of less than 10-4 in both blood and bone marrow aspirate after 4.5 months of treatment with 80 mg/d dose, as measured by European Research Initiative in CLL flow cytometry assay with 10-4 sensitivity. Conclusion: These results demonstrated that BGB-11417 is effective and well tolerated at all tested doses, with no increase in AEs with increasing dose. Dose escalation is still ongoing because an MTD has not yet been reached in any dose-escalation cohort as of the data cutoff date, with patients being recruited. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase Ib study of pembrolizumab in combination with trastuzumab emtansine for metastatic HER2-positive breast cancer

BackgroundPreclinical and clinical data support potential synergy between anti-HER2 therapy plus immune checkpoint blockade. The safety and tolerability of trastuzumab emtansine (T-DM1) combined with pembrolizumab is unknown.MethodsThis was a single-arm...

ABCL-052 MINDway: A Phase Ib/II Dose Optimization Study to Assess Safety and Pharmacokinetics of Tafasitamab + Lenalidomide in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

The chemo-free immunotherapy tafasitamab + lenalidomide has been granted FDA accelerated approval and EU conditional marketing authorization for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) treatment in autologous stem cell transplant-ineligible adults. Treatment schedule optimization aims to reduce the frequency of hospital visits and decrease treatment burden and healthcare utilization. MINDway (NCT05222555) will investigate if tafasitamab administration at levels higher than the approved 12 mg/kg dose at a reduced dosing frequency maintains the benefit-risk relationship of tafasitamab + lenalidomide for patients with R/R DLBCL. To assess an optimized tafasitamab treatment schedule in patients with R/R DLBCL. Open-label, multicenter, Phase Ib/II study. Currently enrolling; the planned sample size is 51 patients. Eligible patients are aged 18-80 years with histologically confirmed R/R DLBCL and 1-3 prior systemic regimens, including CD20-targeted therapy. Patients previously treated with CD19-targeted therapy or immunomodulatory imide drugs, such as lenalidomide, are excluded. The modified dosing regimen will be investigated in a stepwise design: two sequential dose-finding cohorts (planned n=6 each) followed by an expansion cohort (planned n=39). Lenalidomide 25 mg will be administered in all cohorts on Days 1-21 of each 28-day cycle for up to 12 cycles. After Cycle 12, patients will continue tafasitamab monotherapy at the assigned dosing regimen until progression. After reviewing safety and pharmacokinetic data from Cohorts 1 and 2, patients will be enrolled in an expansion cohort to receive tafasitamab + lenalidomide (tafasitamab dose: 24 or 30 mg/kg) for further evaluation. No intra-patient dose escalation from 24 to 30 mg/kg is permitted. The primary endpoints are the incidence and severity of treatment-emergent adverse events. Key secondary endpoints are tafasitamab serum concentration after 3 and 12 cycles, best objective response rate, duration of response, and progression-free survival. Not yet available. MINDway will evaluate an optimized tafasitamab dosing regimen to reduce the frequency of hospital/clinic visits for tafasitamab-treated patients with R/R DLBCL. Reducing the frequency of visits by half is expected to reduce patient burden and support long-term treatment compliance. Fewer visits may result in less exposure to hospital infections in this already susceptible population. MorphoSys AG.

PB2112: MINDWAY: A PHASE IB/II DOSE OPTIMIZATION STUDY TO ASSESS SAFETY AND PHARMACOKINETICS OF TAFASITAMAB + LENALIDOMIDE IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA

Background: Tafasitamab is an Fc-enhanced, humanized, anti-CD19 monoclonal antibody which, in combination with the immunomodulatory drug lenalidomide, has been granted accelerated FDA approval and EU conditional marketing authorization based on results from L-MIND (NCT02399085) for the treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in adult patients ineligible for autologous stem cell transplant. Treatment schedule optimization aims to reduce the frequency of hospital visits and decrease treatment burden and healthcare utilization while maintaining clinical benefits. Aims: MINDway (NCT05222555) will investigate if administration of tafasitamab at levels higher than the approved 12 mg/kg dose at a reduced dosing frequency can maintain the benefit-risk relationship of tafasitamab + lenalidomide treatment for patients with R/R DLBCL. Methods: MINDway is an open-label, multicenter, Phase Ib/II study in patients aged 18‒80 years with histologically confirmed DLBCL and R/R status after at least one, but no more than three, prior systemic regimens, including CD20-targeted therapy. Patients previously treated with CD19-targeted therapy or with immunomodulatory imide drugs such as lenalidomide are excluded. The modified tafasitamab dosing regimen will be investigated in a stepwise design with two sequential dose-finding cohorts (planned n=6 each) followed by an expansion cohort (planned n=39; Figure). Lenalidomide 25 mg will be administered in all cohorts on Day (D) 1‒21 of each 28-D cycle for up to 12 cycles. After Cycle 12, patients will continue tafasitamab monotherapy at the assigned dosing regimen until progression. Following a review of the safety and pharmacokinetic data from Cohorts 1 and 2, patients will be enrolled in an expansion cohort to receive tafasitamab + lenalidomide at the tafasitamab dose of 24 mg/kg or 30 mg/kg for further evaluation. No intra-patient dose escalation from 24 mg/kg to 30 mg/kg is permitted. The primary endpoint is the incidence and severity of treatment-emergent adverse events; key secondary endpoints include tafasitamab serum concentrations after 3 and 12 treatment cycles and best objective response rate, duration of response, and progression-free survival by investigator assessment. All endpoints will be analyzed using descriptive statistics; no formal statistical tests will be performed. MINDway is currently enrolling, with a planned sample size of 51 patients. Results: Results for this study are not yet available: outcome data as described above will be presented in due course. Image:Summary/Conclusion: MINDway will optimize the tafasitamab dosing regimen to reduce the frequency of hospital/clinic visits for tafasitamab treated R/R DLBCL patients. Reducing the overall frequency of clinic visits by half is expected to reduce the patient burden and support long-term treatment compliance. Furthermore, given the severity of the disease, reduced hospital visits may result in less exposure to hospital infections in this already susceptible population.

A phase 1 study of serplulimab, a novel humanized monoclonal anti-PD-1 antibody, in patients with advanced solid tumors.

e14560 Background: Serplulimab, a novel humanized IgG4 monoclonal antibody against PD-1 receptor, increased functional activities of human T cells and showed anti-tumor activity in several xenograft models. This phase 1 study was designed to assess the safety and tolerability of serplulimab in patients with metastatic or recurrent solid tumors. Methods: This prospective, open-label, two-cohort (dose-finding cohort [up to 30 patients]; dose expansion cohort [up to 27 patients]) phase 1 study was conducted in patients with metastatic or recurrent solid tumors who had failed standard therapy. In the dose-finding cohort, Bayesian optimal interval (BOIN) design was adopted to explore the MTD of serplulimab. Patients were administered serplulimab (Q2W) at doses of 0.3, 1, 3, or 10 mg/kg via intravenous infusion until disease progression, the maximum of 1 year, withdrawal from the study, or death, whichever occurred first. In the dose expansion cohort, nine eligible patients were enrolled in each dose group to receive fixed doses of serplulimab at 200 (Q2W), 300 (Q3W) or 400 mg (Q4W). The primary objective of this study was to identify the safety profile and the MTD of serplulimab. The PK profile and the preliminary efficacy were also examined as secondary objectives. Results: Here we only report the results from the dose-finding cohort. As of July 27, 2020, 29 patients were enrolled and treated with at least one dose of serplulimab (0.3 mg/kg group, n = 3; 1 mg/kg group, n = 4; 3 mg/kg group, n = 6; 10 mg/kg group, n = 16). At baseline, the mean age of enrolled patients was 60.0 years, with a mean BMI of 24.7 kg/m2, a mean BSA of 1.7 m2, and a mean LVEF of 67.1%. All patients presented with stage IV tumors at baseline, among whom 79.3% were diagnosed with metastatic disease. Only one patient in the 3 mg/kg dose group experienced DLTs, which was reported during the first cycle. The MTD was not determined yet. Overall, 28 (96.6%) patients experienced at least one TEAE during the study, mostly of grade 1 or 2. No notable differences were observed among the dose groups with regard to the incidence of TEAEs. The most frequently reported TEAEs was decreased appetite (41.4%), fatigue (31.0%), nausea (27.6%), pyrexia (27.6%), and pleural effusion (27.6%). Minimal accumulation of serplulimab was observed following multiple dose administrations. The preliminary anti-tumor efficacy of serplulimab was demonstrated by a DCR of 60.0%, an ORR of 8.0%, and a median PFS of 107.0 days. Conclusions: In summary, serplulimab up to 10 mg/kg was well tolerated and showed promising anti-tumor activity in patients with metastatic or recurrent solid tumors. Serplulimab is currently being investigated in phase 3 studies among patients with NSCLC, SCLC, esophageal cancer, mCRC, etc. Clinical trial information: NCT03468751.

A Multicenter, Single-Arm, Phase I/II Dose Finding and Efficacy Study of Venetoclax, CC-486, and Obinutuzumab in Minimally-Pretreated Follicular Lymphoma

KC and ML are co-first authors.Background:Follicular lymphoma (FL) is the most common indolent B-cell lymphoma and has a relapsing and remitting course with risk of transformation to aggressive disease. Long-term toxicity can accumulate with repeated exposure to palliative cytotoxic chemotherapy. Rationally targeted agents have demonstrated disease control with limited toxicity in hematologic malignancies, representing a potential chemotherapy-sparing option.BCL2 rearrangements leading to overexpression are nearly universal in FL, but BCL2 inhibition monotherapy has disappointing efficacy in FL. Potential reasons include known resistance mechanisms, such as MCL-1 overexpression, or redundant survival pathways. Founder mutations in FL often involve epigenetic regulation, and BCL2 rearrangements are necessary but not sufficient for FL lymphomagenesis. In patients with FL, abnormal DNA methylation programming cooperates with somatic mutations to drive lymphomagenesis. The resulting epigenetic deregulation may be targetable by hypomethylating agents, including azacitadine (AZA). There are no published studies of venetoclax and AZA in preclinical models of FL, but there are extensive preclinical data in acute myeloid leukemia. AZA is an epigenetic modulator with synergistic anti-leukemic effect when paired with venetoclax. Treatment with AZA results in MCL-1 downregulation, which may abrogate FL resistance to BCL2 inhibition. AZA also induces re-expression of CD20 and re-sensitizes FL patients to anti-CD20 therapy. In lymphoma xenograft models, the combination of obinutuzumab and venetoclax causes more tumor growth inhibition compared to rituximab with venetoclax, possibly from more potent direct cytotoxicity.These preclinical studies suggest that epigenetic modulation of FL cells with AZA may increase the sensitivity to BCL2 inhibition and anti-CD20 therapy. The foundational position of epigenetic dysregulation in the clonal evolution of FL suggests the optimal time for this strategy may be early in the course of the disease. We hypothesize that a safe and tolerable dose of venetoclax, CC-486 (oral AZA), and obinutuzumab can be found with treatment efficacy equal to or better than other non-chemotherapy agents in the frontline treatment of FL. We present a dose-finding and efficacy trial of venetoclax, CC-486, and obinutuzumab in minimally pre-treated FL patients.Study Design:This is a single arm, multi-center phase I/II clinical trial (Figure 1). The dose finding phase is a 3+3 design with 3 escalating dose levels and two optional de-escalation levels (12-18 patients). Venetoclax (400-800mg) will be given days 1-28 of each 28 day cycle; CC-486 (150-200mg) will be given days 1-14; and obinutuzumab will be given at a fixed dose of 1000mg on days 1, 8, and 15 of cycle 1 and then day 1 of each subsequent cycle. Venetoclax and CC-486 will be given up to 12 cycles and obinutuzumab for a total of 9 cycles. Once the recommended phase 2 dose (RP2D) is identified, the study will proceed to a Simon two-stage expansion cohort. In this cohort, a three month “window” of the doublet venetoclax and CC-486 prior to introduction of obinutuzumab at cycle 4 will allow an assessment of activity of the two-drug combination. Obinutuzumab is given on days 1, 8, and 15 of cycle 4, and day 1 of each subsequent cycle. Key inclusion criteria are: age ≥ 18, ECOG ≤2; adequate kidney/liver function; and grade 1-3a FL with an indication for treatment who are either untreated or have ≤2 courses (16 doses) of lifetime anti-CD20 therapy. Patients with clinical or histologic evidence of FL transformation are excluded. Up to 32 patients will be enrolled to test the null hypothesis of a 30% CR rate against a 50% alternative (80% power, one-sided alpha=0.10).The primary objectives are the RP2D and safety based on adverse events for the dose-finding cohort, and the CR rate by PET in the expansion cohort. Secondary objectives include progression free survival, overall survival, effect of 3 cycles of venetoclax/CC-486 in the window design of the expansion cohort, and CR rate at 30 months post-treatment with PET. Exploratory objectives include pre-treatment mutation biomarkers, minimal residual disease by circulating tumor DNA, and circulating cell-free DNA methylation patterns. This trial design was reviewed and revised at ASH CRTI. Recruitment is ongoing and this trial is registered with ClinicalTrials.gov: NCT04722601. [Display omitted] DisclosuresKline: Kite/Gilead: Speakers Bureau; Seagen: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Research Funding; Verastem: Research Funding; SecuraBio: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees. Smith: Celgene, Genetech, AbbVie: Consultancy; Alexion, AstraZeneca Rare Disease: Other: Study investigator.

Preliminary Results from the Flu/Cy/Alemtuzumab Arm of the Phase I BALLI-01 Trial of UCART22, an Anti-CD22 Allogeneic CAR-T Cell Product, in Adult Patients with Relapsed or Refractory (R/R) CD22+ B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Preliminary Results from the Flu/Cy/Alemtuzumab Arm of the Phase I BALLI-01 Trial of UCART22, an Anti-CD22 Allogeneic CAR-T Cell Product, in Adult Patients with Relapsed or Refractory (R/R) CD22+ B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Preliminary evidence of antitumour activity of Ipatasertib (Ipat) and Atezolizumab (ATZ) in glioblastoma patients (pts) with PTEN loss from the Phase 1 Ice-CAP trial (NCT03673787)

Abstract Aims Despite improved understanding of effector T-cell trafficking into the central nervous system, initial trials with anti-PD1/PD-L1 immune checkpoint inhibitors (ICIs) have failed to meet their primary endpoints. PTEN loss of function is frequent in GBM and has been correlated with not only poor overall prognosis, but also impaired antitumour responses, including reduced T cell infiltration into tumour and reduced efficacy of ICIs. Ipatasertib is a novel, potent, selective, small-molecule inhibitor of Akt. We have shown that Ipatasertib efficiently depletes FOXP3+ regulatory T cells from the tumour microenvironment (TME) resulting in increased infiltration of effector T cells in solid tumours (Lopez 2020, AACR). We hypothesize that the use of AKT inhibition in PTEN glioblastomas may deplete the TME of suppressive immune cells, and render malignant brain tumours more responsive to ICIs. We present updated data for the combination of Ipat+ATZ in patients with glioblastoma. Method Patients with relapsed WHO grade IV GBM with stable neurological symptoms ≥5 days prior to enrolment, requiring &amp;lt;3mg Dexamethasone were recruited into two cohorts of this early phase, open-label, single-centre trial studying the combination of Ipatasertib (Ipat) and Atezolizumab (ATZ): a dose finding cohort (A2; n=9) and an expansion cohort (B3; n=7, recruitment ongoing). The Ice-CAP A2 cohort assessed safety, pharmacodynamic, and preliminary clinical activity of Ipat (200mg or 400mg OD) + ATZ (1200mg Q3W) in pts with potentially resectable relapsed WHO Grade IV GBM. Pts had a 14-21-day run-in phase of Ipat then surgical tumour resection. Combination Ipat+ATZ commenced post surgery. Patients who declined surgery or who were deemed high risk for surgery proceeded directly to combination. Patients in the expansion cohort B3 commenced directly on Ipat+ATZ at the RP2D of 400mg Ipat with ATZ. Results 16 evaluable recurrent GBM pts were enrolled across two cohorts. Median age 56 yrs (25-71 yrs). Median ECOG PS 1. Median lines of prior therapy 1 (range 1-4). 10 pts had PTEN loss by IHC (H&amp;lt;30) and/or PTEN mutations on next generation sequencing. No DLTs, treatment-related (TR) serious adverse events (AEs), or immune-related AEs were observed. Most common TR AEs were G1 diarrhoea (44%), mucositis (17%), rash (28%). Clinical benefit rate (CR, PR and SD&amp;gt; 6 cycles) at clinical cutoff date (23/02/21) in patients with PTEN aberration was 30% (3/10). A 58-year-old man with PTEN loss had MRI at Cycle 5 showing worsening enhancement suggestive of disease progression. Resection of the lesion showed intense lymphocyte infiltration and pathological CR. He is currently on Cycle 22 with no evidence of disease. Two other patients with PTEN loss with radiological stable disease per RANO criteria remain well on study for &amp;gt;6 cycles. Conclusion Combination Ipat+ATZ appears safe and tolerable in GBM pts, with 400mg Ipatasertib OD + 1200mg ATZ Q3W declared as RP2D. Early efficacy signals were detected with PTEN loss being a promising predictive biomarker for response to combination. An expansion cohort enriched with pts with PTEN loss is ongoing.

Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma

AbstractProteins in the antiapoptotic B-cell lymphoma 2 (BCL-2) family play a role in the pathophysiology of multiple myeloma (MM). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis of MM cells, and its efficacy may be potentiated through combination with agents that increase BCL-2 dependency or have complementary mechanisms of action. The safety, tolerability, pharmacokinetics, and antitumor activity of venetoclax in combination with carfilzomib and dexamethasone (VenKd) in adults with relapsed/refractory MM (RRMM) were investigated in this phase 2 dose-escalation study. Oral venetoclax (400 or 800 mg) was administered daily in combination with intravenous carfilzomib (27, 56, or 70 mg/m2) and oral dexamethasone (20 or 40 mg) in 4 dose-finding cohorts. The expansion cohort received venetoclax 800 mg, carfilzomib 70 mg/m2, and dexamethasone 40 mg. Forty-nine patients received treatment. Median prior lines of therapy was 1 (range, 1-3), and median time in the study was 27 months. The most common treatment-emergent adverse events were diarrhea (65%), fatigue (47%), nausea (47%), and lymphopenia (35%). Serious adverse events occurred in 26 (53%) patients. Of 3 treatment-emergent deaths, 1 was considered treatment related. The overall response rate was 80% in all patients, 92% in patients with t(11;14) (n = 13), and 75% in patients without (n = 36). The rate of complete response or better was 41%. Median progression-free survival was 22.8 months. Treatment with VenKd was well tolerated and showed promising response rates in this RRMM patient population, with greater responses observed in patients with t(11;14). This trial is registered at www.clinicaltrials.gov as #NCT02899052.