Immune priming with nivolumab followed by nivolumab and rituximab in first-line treatment of follicular lymphoma: The phase 2 1st FLOR study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7560-7560
Author(s):  
Eliza Anne Hawkes ◽  
Sze Ting Lee ◽  
Geoff Chong ◽  
Michael Gilbertson ◽  
Andrew Grigg ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Response Rate ◽  
Nk Cell ◽  
Single Agent ◽  
Stage Iv ◽  
Complete Response ◽  
Phase 2 ◽  
Open Label ◽  
Immune Priming ◽  
Biomarker Analysis

7560 Background: Standard of care immunochemotherapy in front-line (1L) follicular lymphoma (FL) is highly efficacious but not without significant toxicity. High rates of grade 3-5 adverse events (AEs), primarily infection and bone marrow suppression, are experienced in up to 75% of patients. A more tolerable but equally effective approach is required. PD-1 inhibition, in combination with rituximab (R), increases T cell anti-tumour effect & enhances NK cell antibody dependent cell cytotoxicity, with proven efficacy in relapsed FL. The concept of ‘priming’ the immune system with nivolumab (N) prior to tumour-directed therapy has rationale and evidence, but the safety of this approach in 1L FL is not described. Methods: ‘1st FLOR’ (NCT03245021) is an open-label, multi-centre, phase 2, Simon’s 2-stage study of N + R (N = 39). Key eligibility were stage III-IV grade 1-3A FL requiring 1L systemic therapy; ECOG ≤2; adequate organ function. All patients (pts) receive induction N 240mg IV 2-weekly for 4 cycles. Pts with complete response (CR) receive 4 further cycles of 240mg IV N monotherapy then 12 cycles of maintenance N 480mg IV 4-weekly. Pts with < CR had 240mg N plus 375mg/m2 IV R 2-weekly for 4 cycles followed by maintenance N+R (N 480mg 4 weekly for 12 cycles; R 12 weekly for 8 cycles). Primary endpoint (EP) was ≥ G3 toxicity rate during induction. Secondary EPs; response rate by Lugano response criteria, overall toxicity, PFS, OS. Results: Between September 2017 to March 2020, 39 pts were enrolled. Baseline characteristics included median age of 54 (range: 28-79). stage IV disease in 67%, B Symptoms & bulk (≥7cm) in 23% each, intermediate-high risk FLIPI in 74%. The primary EP was met, with only 16 pts (41%) having ≥G3 toxicity at end of induction. Non-immune AEs were predominantly G1-2; most commonly infection (67%) & fatigue (64%). G3-4 Immune-related AEs were infrequent and included pancreatitis plus hepatitis (N = 1), pancreatitis alone (N = 1), rash (N = 1), transaminitis (N = 2), hypocortisolism (N = 1), hyperglycaemia (N = 3) and asymptomatic lipase/amylase increase (N = 3). Median follow-up was 17.5 months (range: 7-39). Overall response rate was 92% (36/39) with CR in 54% (21/39). Median time to CR was 5 months (m) (range: 2-25). Nine pts (23%) discontinued treatment; 7 due to progressive disease (1 pt died of transformed FL), 2 developed constitutional symptoms (1 stable disease, 1 partial response). In 25 evaluable pts, 12m PFS & OS is 72% (CI 51-88) & 96% (CI 80-100). Biomarker analysis is in progress. Conclusions: Immune-priming with single-agent N, then combination N+R in 1L FL is associated with favourable toxicity and high ORR & CR rates potentially providing an alternative to chemotherapy. Acknowledgements: Bristol-myers Squibb provided funding and nivolumab for this study. Clinical trial information: NCT03245021.

scholarly journals Safety and activity of pembrolizumab in combination with rituximab in relapsed or refractory follicular lymphoma

2022 ◽  
Author(s):  
Loretta J. Nastoupil ◽  
Collin K Chin ◽  
Jason R Westin ◽  
Nathan H Fowler ◽  
Felipe Samaniego ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Follicular Lymphoma ◽  
Liver Enzyme ◽  
Response Rate ◽  
Progression Free Survival ◽  
Complete Response ◽  
Low Grade ◽  
Phase 2 ◽  
Open Label ◽  
Grade 3

PD-1 blockade enhances the function of anti-tumor T-cells and antibody-dependent cell-mediated cytotoxicity (ADCC) of NK cells. In a single-center, open-label, phase 2 trial, we tested the combination of pembrolizumab, an anti-PD-1 monoclonal antibody and rituximab, an anti-CD20 monoclonal antibody that induces ADCC, in 30 follicular lymphoma (FL) patients with rituximab-sensitive disease who relapsed after ≥1 prior therapy. Pembrolizumab was administered at 200mg IV every 3 weeks for up to 16 cycles and rituximab was given at 375mg/m2 IV weekly for 4 weeks in cycle 1 only. The most common grade 3/4 adverse events (AE) were liver enzyme abnormalities (3%), diarrhea (3%), nausea (3%), aseptic meningitis (3%) and pancreatitis (3%). Low-grade immune-related AEs were reported for 80% of patients, including diarrhea (43%), liver enzyme abnormalities (33%), thyroid dysfunction (27%), and rash (23%). Grade 3 or 4 immune related AEs occurred in 13% of patients. Treatment-related AEs led to discontinuation in 6 (20%) patients. Overall response rate (primary endpoint) was 67% and complete response rate was 50%. Median progression-free survival (PFS) was 12.6 months (95% CI, 8.2-27.6 months), the 3-year overall survival rate was 97%, and 23% of patients were in remission at a median follow up of 35 months. Presence of a high CD8+ T-effector score at baseline in the tumor was associated with induction of a complete response and improved PFS. In this single arm, phase 2 study, the combination of pembrolizumab and rituximab demonstrates favorable efficacy and safety profile in relapsed FL. This trial is registered at www.clinicaltrials.gov: NCT02446457.

Obinutuzumab short-duration infusion (SDI) in previously untreated advanced follicular lymphoma: Results from the end of induction analysis of the phase IV GAZELLE study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7545-7545
Author(s):  
Miguel Angel A. Canales Albendea ◽  
Thomas A. Buchholz ◽  
Koji Izutsu ◽  
Takayuki Ishikawa ◽  
Laura Maria Fogliatto ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Complete Response ◽  
Primary Analysis ◽  
Open Label ◽  
Secondary Endpoints ◽  
To Receive ◽  
Phase Iv

7545 Background: Obinutuzumab (G)-chemotherapy (chemo) has demonstrated improved progression-free survival compared with rituximab (R)-chemo in previously untreated advanced follicular lymphoma (FL). G is currently administered by IV infusion over ̃3–4 hours. A shorter duration of infusion in Cycle (C) 2 and subsequent cycles, as is standard practice with R, could improve convenience for patients (pts) and efficiency for infusion facilities. We report the primary analysis of the prospective, open-label, multicenter, single-arm, Phase IV, GAZELLE study (NCT03817853), which evaluated the safety of G administered as a 90-minute (min) SDI from C2 onwards in pts with FL. Methods: Pts with previously untreated FL received G (1000mg) intravenously on Day (D) 1, 8, and 15 of C1, and on D1 thereafter, plus chemo (bendamustine, CHOP, or CVP) for 6–8 cycles. In C1, pts received G at the standard infusion rate. Pts without a Grade (Gr) ≥3 infusion-related reaction (IRR) in C1 were eligible to receive G as a 90-min SDI from C2. Pts with a Gr 3 IRR in C1 received the standard G infusion in C2, and were eligible for G SDI in subsequent cycles if no Gr ≥3 IRRs occurred. Pts with a second Gr 3/4 IRR discontinued G. At the end of induction (EOI), responding pts received maintenance G (1000mg) as SDI for 2 years or until disease progression (PD). The primary endpoint was incidence of Gr ≥3 IRRs during C2. IRRs were defined as any event occurring ≤24 hours from infusion judged to be related to treatment. Secondary endpoints included adverse events (AEs) and investigator-assessed overall response rate at EOI. Results: As of December 3, 2020, 113 pts had received study treatment. Median age was 62.0 years, 50.4% were male, 61.9% had stage IV FL, and 45.1% were classified as high-risk FLIPI. Of the 110 pts who were eligible for G SDI from C2, no pt experienced a Gr ≥3 IRR with SDI in C2 (Table). One pt experienced a Gr 3 IRR with SDI in C5, presenting hypertension. All other IRRs with SDI were Gr 1/2. No Gr 4/5 IRRs were reported. Other AEs were similar to those observed in previous studies. At the clinical cut-off date, 104 pts had a CT imaging-based response assessment at EOI and 9 pts had no response assessment; 76/113 (67.3%) had a complete response, 22 (19.5%) had a partial response, and six (5.8%) had PD. Conclusions: In GAZELLE, G SDI in C2 and beyond appeared to be safe. No Gr 3 IRRs were observed in C2 and only one Gr 3 IRR was reported in subsequent cycles. The safety profile of G SDI was comparable with the established profile of G in advanced FL. Clinical trial information: NCT03817853. [Table: see text]

scholarly journals Temsirolimus Has Activity in Non–Mantle Cell Non-Hodgkin's Lymphoma Subtypes: The University of Chicago Phase II Consortium

2010 ◽  
Vol 28 (31) ◽  
pp. 4740-4746 ◽  
Author(s):  
Sonali M. Smith ◽  
Koen van Besien ◽  
Theodore Karrison ◽  
Janet Dancey ◽  
Peter McLaughlin ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Mantle Cell ◽  
Group A ◽  
Group B ◽  
Indolent Lymphomas

PurposeDespite high initial remission rates, most lymphomas relapse and require further therapy. The mammalian target of rapamycin (mTOR) pathway is a validated target in mantle cell lymphoma, but has not been extensively evaluated in other lymphomas.Patients and MethodsWe performed a phase II trial of single-agent temsirolimus 25-mg weekly in patients with relapsed aggressive and indolent lymphomas. The primary objective was overall and complete response rate. Patients were stratified by histology: group A (diffuse large B-cell lymphoma, transformed follicular lymphoma), group B (follicular lymphoma), and group C (chronic lymphocytic leukemia/small lymphocytic lymphoma, and other indolent lymphomas).ResultsEighty-nine patients were treated, with outcome strongly dependent on histology. Group A had an overall and complete response rate of 28.1% and 12.5%, respectively, and median progression-free survival (PFS) of 2.6 months and median overall survival (OS) of 7.2 months. Group B had overall and complete response rates of 53.8% and 25.6%, respectively, and median PFS of 12.7 months; median OS has not yet been reached. Group C had a partial response rate of 11% with no complete responders. Toxicity was mainly mild and/or reversible myelosuppression and mucositis; however, four patients developed pneumonitis.ConclusionsSingle-agent temsirolimus has significant activity in both diffuse large B-cell lymphoma and follicular lymphoma, although the durability of responses and PFS are longer for patients with follicular lymphoma. This is the first report of substantial activity of temsirolimus in lymphomas other than mantle cell lymphoma, and supports further evaluation of mTOR as a target in these diseases.

Randomized phase II study of the safety and efficacy of a human anti-αv integrin monoclonal antibody (CNTO 95) alone and in combination with dacarbazine in patients with stage IV metastatic melanoma: 12-month results

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9029-9029
Author(s):  
C. Loquai ◽  
A. Pavlick ◽  
D. Lawson ◽  
R. Gutzmer ◽  
J. Richards ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Research And Development ◽  
Metastatic Melanoma ◽  
Single Agent ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Complete Response ◽  
Open Label ◽  
Safety And Efficacy ◽  
To Receive

9029 Objectives: Evaluate the safety and efficacy of CNTO 95, a human anti-αv integrin monoclonal antibody, when administered alone or in combination with dacarbazine (DTIC). Methods: Patients with Stage IV metastatic melanoma were randomized 1:1:1:1 to receive 5 or 10mg/kg CNTO 95 alone, or DTIC (1000mg/m2) + either 10mg/kg CNTO 95 or placebo administered intravenously once every 3 weeks for 8 cycles in the absence of disease progression or unacceptable toxicity. DTIC arms were blinded; single-agent arms were open-label. The primary endpoint was progression free survival (PFS); secondary endpoints included partial response (PR), complete response (CR), stable disease (SD) and overall survival (OS). Major safety endpoints included the incidence of adverse events (AEs) and serious AEs (SAEs). Results: Patients were randomized to receive 5mg/kg CNTO 95 (n=32), 10mg/kg CNTO 95 (n=33), CNTO 95+DTIC (n=32), or placebo+DTIC (n=32). Baseline demographics were similar across groups. The median PFS for CNTO 95+DTIC was 75 days, placebo+DTIC was 54 days and both CNTO 95 alone arms were 42 days. Six patients achieved PR (2–10mg/kg CNTO 95, 1-CNTO 95+DTIC, 3-placebo+DTIC); one patient achieved CR (CNTO 95+DTIC). A higher proportion (43.3%) of patients achieved SD ≥ 12 wks in the CNTO 95+DTIC group compared with the other 3 groups (<20.0%). The median survival was 11.0 months for the patients in the CNTO 95+DTIC arm, 9.8 months and 14.9 months for the 5mg/kg and 10mg/kg arms, and 8.0 months for those in the DTIC control arm. The most common AEs were headache, nausea, fatigue, pyrexia, vomiting and transient uveitic reactions. Three patients (1–5mg/kg, 2-CNTO 95+DTIC) discontinued treatment due to AEs. A higher proportion of patients experienced SAEs in the placebo+DTIC group (29.0%) than in the 5mg/kg (12.9%), 10mg/kg (16.2%) or CNTO 95+DTIC (18.8%) groups. Conclusions: CNTO 95 alone or combined with DTIC was generally well tolerated. In patients with Stage IV metastatic melanoma, a trend toward improvement in PFS, OS and disease control was demonstrated with CNTO 95+DTIC. Centocor, Centocor Research and Development, Inc. Centocor Research and Development, Inc. Johnson & Johnson Centocor Research and Development, Inc. No significant financial relationships to disclose.

Rituximab in Combination With Fludarabine Chemotherapy in Low-Grade or Follicular Lymphoma

2005 ◽  
Vol 23 (4) ◽  
pp. 694-704 ◽  
Author(s):  
M.S. Czuczman ◽  
A. Koryzna ◽  
A. Mohr ◽  
C. Stewart ◽  
K. Donohue ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Response Rate ◽  
Complete Response Rate ◽  
Complete Response ◽  
Infectious Complications ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Similar Response ◽  
Open Label ◽  
Treatment Naïve

Purpose To evaluate the safety and efficacy of fludarabine plus rituximab in treatment-naïve or relapsed patients with low-grade and/or follicular non-Hodgkin's lymphoma. Patients and Methods This was an open-label, single-arm, single-center phase II study enrolling 40 patients. During the first week of the study, patients received two infusions of rituximab 375 mg/m2 administered 4 days apart. Seventy-two hours after the second infusion of rituximab, patients received the first of six cycles of fludarabine chemotherapy (25 mg/m2/d for 5 days on a 28-day cycle). Single infusions of rituximab were administered 72 hours before the second, fourth, and sixth cycles of fludarabine, and two infusions of rituximab were given 4 weeks after the last cycle of fludarabine. Treatment duration was 26 weeks. Results An overall response rate of 90% (80% complete response rate) was achieved in the intent-to-treat population. Similar response rates were seen in treatment-naïve and previously treated patients. The median duration of response has not been reached at 40+ months. The median follow-up time in this study is 44 months (range, 15 to 66 months). In patients positive for the 14;18 translocation in blood and/or marrow at enrollment, molecular remission was achieved in 88% of cases, with patients remaining negative for up to 4 years to date. Hematologic toxicity was manageable, and except for a 15% incidence of herpes simplex/zoster infections, infectious complications were rare. Nonhematologic toxicities were minimal. Conclusion Rituximab plus fludarabine was well tolerated and associated with an excellent complete response rate, including molecular remissions, in patients with low-grade or follicular lymphoma.

Phase 2 trial of talabostat and cisplatin in patients with stage IV melanoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8040-8040 ◽  
Author(s):  
C. Cunningham ◽  
A. C. Pavlick ◽  
K. D. Khan ◽  
G. Frenette ◽  
S. O’Day ◽  
...  
Keyword(s):  
T Cell ◽  
Organ Failure ◽  
Oral Delivery ◽  
Single Agent ◽  
Stage Iv ◽  
Phase 2 ◽  
Open Label ◽  
Eligibility Criteria ◽  
Cell Immunity ◽  
Stage Iv Melanoma

8040 Background: Talabostat (TAL) is an oral inhibitor of dipeptidyl peptidases such as fibroblast activation protein found on the stroma of tumors, draining lymph nodes, and in melanomas. TAL up-regulates cytokines and chemokines, leading to specific T-cell immunity and T-cell independent activity. TAL significantly enhances the activity of cisplatin (C) in mice, and reduces tumor size >60% in melanoma xenografts (A375, A2058). This trial evaluated the activity of TAL and C in patients with Stage IV melanoma. Methods: Open-label, single-arm, Phase 2 study of 4 x 3-week cycles of C-75mg/m2 (Day 1) and TAL-300mcg BID orally on Days 2–15 with dose-escalation to TAL-400mcg BID depending on tolerability. Single-agent TAL could be continued beyond 4 cycles until disease progression or unacceptable toxicity. Eligibility criteria included: ≤1 prior bio- or chemotherapy regimen, ECOG 0–2, measureable disease per RECIST, no symptomatic CNS metastases, LDH, ALT, and AST <3X ULN. Primary endpoint was disease response; secondary endpoints included PFS, duration of response, and survival. Results: 74 patients (50 men, 24 women) entered the study; median age was 58 years (range 27 to 79); 94.6% were caucasian. Most patients (71.4%) were M1c, and the majority (64.3%) had received at least 1 prior regimen; 72.9% of these had received prior cytokine treatment. A PR was reported in 5/42 evaluable patients (11.9%), and SD for at least 4 cycles in an additional 21/42 (50%). Median PFS and survival are currently estimated at 2.6 months (95% CI 2.1, 3.4) and 8.5 months (95% CI 5.4, infinity), respectively in the ITT population. Most frequent AEs were nausea (46%), fatigue (35%), and vomiting (34%); the high unevaluability rate patients was due to non-compliance related to C-associated N/V (thus the dose of C was reduced mid-study from 100 to 75mg/m2). Grade 3 toxicities were neutropenia, fatigue, and dehydration, all at 3.4%. Grade 4 toxicities were organ failure, renal failure, and PD (1 patient each). 4 patients died due to PD, and 1 each due to renal and organ failure. Conclusions: The combination of TAL and C is active in patients with Stage IV melanoma. Most AEs were related to C-associated nausea and vomiting, limiting the oral delivery of TAL. Additional studies of TAL in melanoma with other drug combinations are warranted. [Table: see text]

Results of a Prospective Randomised Open Label Phase III Study Comparing Rituximab Plus Mitoxantrone, Chlorambucile, Prednisolone Chemotherapy (R-MCP) Versus MCP Alone in Untreated Advanced Indolent Non-Hodgkin’s Lymphoma (NHL) and Mantle-Cell-Lymphoma (MCL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 584-584 ◽  
Author(s):  
Michael Herold ◽  
Rita Pasold ◽  
Stefanie Srock ◽  
Sabine Neser ◽  
Dietger Niederwieser ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Response Rate ◽  
Single Agent ◽  
Complete Response ◽  
Phase Iii ◽  
Published Data ◽  
Event Free Survival ◽  
Serious Adverse Events ◽  
Free Survival ◽  
Phase Ii Studies

Abstract Rituximab proved to be effective in relapsed and refractory indolent NHL as a single agent and generated impressive results in phase II studies in combination with chemotherapy. In a prospective randomized trial we compared the efficacy and toxicity of rituximab (375 mg/m² d 1) plus MCP-chemotherapy ( mitoxantrone 8 mg/m² d 3 + 4, chlorambucile 3 x 3 mg/m² d 3 – 7, prednisolone 25 mg/m² d 3 – 7 ) given every 28 days for a total of 8 cycles versus MCP (d 1 – 5) x 8 cycles alone in advanced indolent NHL and MCL. Efficacy endpoints included overall and complete response rates, event free survival, progression free survival, overall survival and toxicity. For response assessment classical definitions have been used. Between 10/98 and 09/03 we randomized 358 patients (pts) with advanced stage follicular lymphoma (FL) (grade 1 + 2), lymphoplasmacytic lymphoma and MCL to either R-MCP or MCP. The study arms are well balanced for all demographic factors. 201/358 pts (56%) had FL. Both regimens were well tolerated with a low incidence of serious adverse events. The overall response rate (RR) and the complete response rate (CR) for all pts was 85,5% and 42% in the R-MCP arm versus 65,5% and 20% in the MCP arm (p<0,0001). Results were even more impressive in the subgroup of FL pts (n=201) with an overall RR of 92,4% and a CR rate of 49,5% for R-MCP versus 75% and 25% for MCP alone respectively (p<0,0001). In the overall group event free survival (EFS) was significantly prolonged for pts receiving R-MCP vs MCP alone (p<0,001). Median EFS for MCP was 19 months, at this time point EFS for R-MCP was 73%. In FL pts the median EFS for MCP is 19 months too and EFS was 86% for R-MCP at this point. 2-year EFS for all pts was 69% for R-MCP versus 44% for MCP; for FL pts the respective 2-year EFS was 83% for R-MCP and 43% for MCP (p’s<0,0001) (Kaplan Maier estimates). These results compare favourably with the recntly published data of immunochemotherapy for treatment of NHL or MCL. The results from our study confirm the superiority of a combination of rituximab and chemotherapy in the first- line treatment of indolent NHL, primarily follicular lymphoma. The CR rates achieved with the R-MCP regimen are impressive, especially since stricter response criteria were used. In summary we conclude, that the addition of rituximab to MCP chemotherapy improves significantly the outcome of pts with indiolent NHL and MCL.

A Phase 2, Open-Label, Multicenter Study of Tazemetostat in Combination with Rituximab for the Treatment of Relapsed or Refractory Follicular Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-4 ◽  
Author(s):  
Krish Patel ◽  
Neil Bailey ◽  
John M. Pagel
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Multicenter Study ◽  
Systemic Therapy ◽  
Single Agent ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Open Label

Background: Patients with follicular lymphoma (FL) who do not achieve a response after 2 or more prior lines of systemic therapy have a poor prognosis when treated with salvage chemotherapy alone or PI3K inhibitors. Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that supports germinal center (GC) formation and suspends differentiation during B-cell development by silencing genes that limit proliferation and promote exit from the GC. Throughout the pathogenesis of FL, EZH2 plays a consistent underlying role in maintaining the GC and B-cell proliferation, regardless of the oncogenic drivers. Dysregulation of EZH2 or gain-of-function mutations in EZH2 can lead to accumulation of malignant B cells and may contribute to the development of FL. Tazemetostat, a first-in-class oral EZH2 inhibitor, recently gained approval by the US Food and Drug Administration in patients with relapsed or refractory (R/R) FL after demonstrating single-agent, antitumor activity in patients with mutant (MT) or wild-type (WT) EZH2 R/R FL. Here we examine the efficacy and safety of tazemetostat in combination with rituximab for the treatment of R/R FL. Study Design and Methods: This trial is a phase 2, single-arm, open-label, multicenter study of tazemetostat in combination with rituximab in patients with R/R FL who have received at least 2 prior lines of systemic therapy, including an anti-CD20-based regimen. Patients eligible for inclusion are aged ≥18 years with grade 1 to 3A FL who have met Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria to receive treatment, have an Eastern Cooperative Oncology Group (ECOG) score ≤2, have &gt;5.0 x 109/L circulating malignant cells, and have not received any prior treatment with EZH2 inhibitors. Patients with transformed FL, a history of clinically significant gastrointestinal conditions, or any uncontrolled illness are excluded from this study. EZH2 mutation testing will be performed during patient screening. Patients will receive tazemetostat 800 mg by mouth twice daily beginning on cycle 1 day 1 for continuous 28-day cycles until the end of cycle 24, for a total of 24 months of therapy. Patients will also receive rituximab 375 mg/m2 intravenously (IV) on cycle 1 day 1, then 375 mg/m2 IV or 1400 mg subcutaneously on days 8, 15, and 22 of cycle 1, and on day 1 of cycles 3, 4, 5, and 6, for a total of 8 doses of rituximab. The primary endpoint is the objective response rate (ORR; the proportion of patients with complete or partial response) in patients with WT EZH2. Key secondary endpoints include median progression free survival (PFS) in patients with WT EZH2; median PFS in all patients, regardless of mutational status; ORR in patients with MT EZH2; efficacy outcomes in rituximab-refractory patients; and incidence of adverse events. Efficacy and safety analyses will be performed on all patients who receive ≥1 dose of study drug. The evaluation of ORR will be based on Lugano 2014 response criteria and will be presented with corresponding 2-sided Clopper-Pearson 95% confidence intervals. The Kaplan-Meier method will be used to estimate PFS. Survival follow-up will be done following the study treatment period every 6 months for 2 years or until disease progression or death for all patients who complete the 24 months of tazemetostat therapy. Disclosures Patel: Adaptive Biotechnologies, AstraZeneca, Pharmacyclics, Janssen, Genentech, Celgene/BMS, BeiGene, Kite: Consultancy. Pagel:Gilead, Pharmacyclics LLC, an AbbVie Company, and AstraZeneca: Consultancy.

COMBAT-CRPC: Concurrent administration of bipolar androgen therapy (BAT) and nivolumab in men with metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5014-5014
Author(s):  
Mark Christopher Markowski ◽  
Mary-Ellen Taplin ◽  
Rahul Raj Aggarwal ◽  
Hao Wang ◽  
Aliya Lalji ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Primary Endpoint ◽  
Radiographic Progression ◽  
Response Rate ◽  
Single Agent ◽  
Phase 2 ◽  
Castration Resistant Prostate Cancer ◽  
Absolute Increase ◽  
Castration Resistant ◽  
Biomarker Analysis

5014 Background: During BAT, intramuscular (IM) testosterone (T) is administered, which results in rapid cycling of serum T levels from supraphysiologic to near-castrate in men with metastatic castration resistant prostate cancer (mCRPC). We previously observed anecdotal clinical responses to immune checkpoint blockade (ICB) in mCRPC patients (pts) previously treated with BAT and hypothesized that that a BAT/ICB combination would be synergistic. Here we report a prospective phase 2 study of men with mCRPC treated with BAT in combination with nivolumab. Methods: This was a multi-center, single arm, open label phase 2 trial (NCT03554317) of men with mCRPC who received T cypionate 400mg IM (BAT) every 28 days and nivolumab 480mg IV every 28 days. LHRH agonist treatment was continued. All pts received BAT as single agent therapy for a 12-week lead-in prior to the addition of nivolumab. Eligible pts were those with asymptomatic mCRPC who had soft tissue disease amenable to biopsy and progressed on at least one prior novel AR targeted therapy. Up to one line of chemotherapy was allowed for the treatment of mCRPC disease. The primary endpoint was confirmed PSA50 response rate. Key secondary endpoints included safety, objective response rate (ORR), and radiographic progression-free survival (rPFS). The trial was designed to detect a 20% absolute increase in PSA50 response rate from the null of 25%. Results: 45 pts were enrolled on study and treated. The confirmed PSA50 response rate was 40.0% (N=18/45, 95% CI: 26-56%, P=0.02 against the 25% null hypothesis). For pts with measureable disease, the ORR was 23.8% (N=10/42). Median rPFS on BAT and nivolumab was estimated at 5.7 months (95% CI: 4.9-7.8 months). 11.1% (N=5/45) of pts were free from radiographic progression for 11 or more months. One patient achieved a complete radiographic response, which is ongoing (>13 months). The majority of adverse events (AE) were Grade <2. The most common AEs were edema (20%), nausea (20%), and back pain (13%). Immune related AE (irAE) were generally mild (Grade <2) with N=2 Grade 3 irAE observed (pericarditis, lipase elevation). Serial biopsies were obtained on trial for translational studies. Conclusions: BAT plus nivolumab was well tolerated without concerning safety signals. The combination met the pre-specified primary endpoint of confirmed PSA50 response in a heavily treated population. Durable responses were observed in a subset of pts. Biomarker analysis is ongoing to identify a molecular signature predictive of response. Clinical trial information: NCT03554317. [Table: see text]

A Phase 2 Trial of Daratumumab and Pembrolizumab in Refractory Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 2-2
Author(s):  
Barry Paul ◽  
James Symanowski ◽  
Paul Osipoff ◽  
Sarah Norek ◽  
Ami P Ndiaye ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Null Hypothesis ◽  
Research Funding ◽  
Response Rate ◽  
Complete Response Rate ◽  
Single Agent ◽  
Progression Free Survival ◽  
Complete Response ◽  
Phase 2 ◽  
Free Survival

Background: Despite significant advances in the treatment of multiple myeloma (MM), it remains an incurable malignancy and novel treatments are still desperately needed. Daratumumab, a human IgG1 anti-CD38 monoclonal antibody, is an essential component of several regimens approved for the treatment of both newly diagnosed (NDMM) and relapsed/refectory myeloma (RRMM), however nearly all patients exposed to this agent eventually acquire resistance. Daratumumab (Dara) has known immunomodulatory effects including reducing CD38-expressing immunosuppressive regulatory B- and T-cells, and CD4+ T-helper cells and CD8+ cytotoxic T-cells, leading to increased CD8+:CD4+ and CD8+:Treg ratios. Additionally, CD38 has been shown to be upregulated in solid tumors which acquire resistance to PD-1/PD-L1 blockade. Pembrolizumab (Pembro) a humanized IgG4 monoclonal PD-1 antibody has previously shown limited clinical activity in combination with the immunomodulatory agents lenalidomide or pomalidomide in early phase trials. Although phase 3 trials did not confirm the benefit of Pembro in combination with immunomodulatory drugs, alternative combinations are being explored in clinical trials. Given their overlapping mechanisms, we hypothesize that the combination of Dara and Pembo will lead to increased anti-myeloma activity while maintaining an acceptable safety profile. Methods: We are conducting a phase 2 single arm trial of the combination of Dara and Pembro in RRMM patients previously treated with 3 or more lines of therapy, including an immunomodulatory agent, proteasome inhibitor, and daratumumab (ClinicalTrials.gov NCT04361851). Subjects will receive Dara-Pembro induction for 6 cycles (Q21 days) followed by Dara-Pembro maintenance until relapse or progression. Dara will be dosed at 16 mg/kg administered intravenously at days 1, 8 and 15 for the first 2 induction cycles and 16 mg/kg at days 1 and 15 of each cycle thereafter. Pembro will be dosed at 200 mg administered intravenously on day 1 of each cycle. Response/progression parameters will be assessed using IMWG criteria. Toxicity will be assessed during treatment via NCI CTCAE v. 4.03. Bone marrow aspirates and serial peripheral blood samples will be collected for correlative studies. The primary endpoint is 8-month progression-free survival (PFS) with response compared to the historical control of single agent daratumumab. Classically, single agent Dara has resulted in a median PFS of 4 months in a similar (although Dara naïve) population which corresponds to an 8-month PFS of 25%. For this population of subjects treated with Dara + Pembro, the aim is to improve the 8-month PFS rate to 50%. An optimum Simon 2-stage design will be used to test the hypothesis that the 8-month PFS rate is less than or equal to 25%. Sixteen subjects will be enrolled in the first stage, and if at least 5 of the 16 patients are alive and progression free at 8 months, an additional 17 subjects will be enrolled (total of 33 subjects). If at least 13 of 33 subjects are alive and progression free at 8 months, the null hypothesis will be rejected. Assuming a one-sided α = 0.05 significance level, this sample size will provide 90% power to reject the null hypothesis, assuming the true 8-month PFS rate is 50%. Key secondary endpoints include overall response rate, clinical benefit rate (minimal response or better), CR (complete response) rate, sCR (stringent complete response) rate, time to response (TTR), time to best response (TTBR), duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety. Safety objectives include dose limiting toxicities and immune-related adverse events (monitored with stopping rules), overall treatment-related adverse events, and a Bayesian-based safety stopping rule for Grade 5 AEs. We also have several translational correlates aimed at identifying molecular subtypes, variants, and neoantigen mutations which may serve as prognostic and predicative immune biomarkers of response to the combination. We also plan to characterize the mechanism(s) of immune exhaustion and T cell dysfunction in RRMM patients. These translational endpoints are aimed to determine patients who would be at highest likelihood to derive benefit from this combination in future studies. Figure 1 Disclosures Paul: Regeneron: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Other: Stock Ownership (prior employee). Atrash:Takeda, Amgen, Karyopharm, BMS, Sanofi, Cellactar, Janssen and Celgene: Honoraria; Amgen, GSK, Karyopharm.: Research Funding; BMS, Jansen oncology, Sanofi: Speakers Bureau. Bhutani:Sanofi Genzyme: Consultancy; Janssen: Other: Clinical Trial Funding to Institute; Takeda: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Prothena: Other: Clinical Trial Funding to Institute; BMS: Other: Clinical trial funding to institute, Speakers Bureau. Voorhees:TeneoBio: Other: Personal fees; Oncopeptides: Other: Personal fees; Levine Cancer Institute, Atrium Health: Current Employment; Adaptive Biotechnologies: Other: Personal fees; Bristol-Myers Squibb: Other: Personal fees; Celgene: Other: Personal fees; Novartis: Other: Personal fees; Janssen: Other: Personal fees. Usmani:GSK: Consultancy, Research Funding; Celgene: Other; Sanofi: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Array Biopharma: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document