Phase I study cohort evaluating an optimized administration schedule of SAR3419, an anti-CD19 DM4-loaded antibody drug conjugate (ADC), in patients (pts) with CD19 positive relapsed/refractory b-cell non-Hodgkin’s lymphoma (NCT00796731).

8057 Background: The recommended dose (RD) of SAR3419 administered intravenously every 3 weeks (q3w) for 6 cycles is 160 mg/m2 and is 55 mg/m2 when administered weekly (q1w) for 8-12 doses. Reversible corneal deposits were dose limiting (DLT) in the q3w schedule. The q1w schedule was well tolerated and active. However, based on the occurrence of late/cumulative adverse events (AE) at the RD supported by pharmacokinetic (PK) analyses showing ADC plasma accumulation after 4 weekly doses, an optimized schedule consisting of 4 weekly doses followed by 4 bi-weekly doses at the RD was tested. Methods: The q1w study was extended to treat 25 pts with the optimized schedule for 8 to 12 doses. Results: Twenty-one pts were evaluable. Main histologies were diffuse large B-cell (DLBCL) (9; 43%) and follicular (6; 29%). Median number of prior regimens was 2 [1-8], 6 pts received prior autologous transplantation and 95% of pts were Ann Arbor stage III-IV at study entry. Median number of doses received was 8 as planned with a median relative dose intensity of 1.0 [0.8-1.0]. Most frequent AEs were asthenia (1 pt with grade 3) and gastrointestinal disorders in 7 pts each. No AE fulfilled the defined DLT criteria. Reversible grade 1 blurred vision/corneal event occurred in 1 pt. Grade 3-4 haematological toxicities were minor consisting of non complicated neutropenia in 4 pts, thrombocytopenia in 2 pts and anemia in 1 pt with no transfusion support. Six (29%) pts, among them 3 with DLBCL, achieved an objective response including 3 CRu (1 in a pt refractory to last regimen). In addition, 9 (43%) pts had stable disease. Response duration was [8-35+] weeks, 5 pts still responding at the cut-off date. Conclusions: The optimized administration schedule shows an improved safety profile compared to prior tested schedules. The clinical efficacy is preserved essentially in aggressive lymphoma. The optimized schedule is being assessed in 2 phase II studies evaluating SAR3419 either as a single agent or in combination with rituximab in pts with DLBCL histology.

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Nivolumab/pembrolizumab in Child-Pugh grade B/C patients with advanced HCC.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16184 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16184-e16184

Author(s):

Jeffrey Sum Lung Wong ◽

Gin Wai Kwok ◽

Vikki Tang ◽

Bryan Li ◽

Roland Ching-Yu Leung ◽

...

Keyword(s):

Single Agent ◽

Objective Response ◽

Median Number ◽

Refractory Ascites ◽

Time To Progression ◽

Advanced Hcc ◽

Grade 3 ◽

Experienced Grade ◽

Systemic Therapies

e16184 Background: Hepatic derangement commonly accompanies advanced HCC (aHCC) and limits the use of systemic therapies. We aimed to evaluate the use of single agent anti-PD-1 nivolumab or pembrolizumab in Child-Pugh (CP) grade B or C patients with aHCC. Methods: Consecutive aHCC patients with CP grade B (CPB) or C (CPC) liver function who received single agent nivolumab or pembrolizumab were analysed. Objective response rate (ORR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed. Results: Between May 2015 and June 2020, 61 patients were included. The median age was 60 (range 28-82). 81% and 4.8% had hepatitis-B and hepatitis-C related HCCs respectively. 72.1% (n = 44) were of CPB and 27.9% (n = 17) were of CPC. Amongst CPB patients, 19 (31.1% of all patients) had CP score 7 (CP7) and 25 (41.0% of all patients) had CP score 8 or 9. The median follow-up was 2.3 months. The ORR of CPB and CPC patients were 6.8% and 0% respectively (p = 0.553). The TTP of CPB and CPC patients were 2.1 months (95% C.I. 1.4-2.8) and 1.4 months (95% C.I. 0.6-2.1) respectively (p = 0.204). CPB patients had significantly better OS than CPC patients (3.1 months (95% C.I. 1.4-4.7), vs. 1.7 months (95% C.I. 1.0-2.4), p = 0.041). Compared to CP score ≥8 (CP≥8) patients, CP7 patients had significantly better OS (median OS CP7 6.7 months (95% C.I. 4.0-9.3), vs. CP≥8 1.8 months (1.2-2.4), p = 0.002). Patients with diuretic-refractory ascites had significantly worse OS compared to those without (1.7 months (95% C.I. 1.0-2.5) vs. 3.7 months (95% C.I. 0.1-7.3), p = 0.004). Portal vein (PV) thrombosis was also significantly associated with inferior survival, with median OS of patients with any PV thrombosis being 1.8 months (95% C.I. 1.0-2.5), compared to 5.3 months (95% C.I. 2.4-8.1) of those without (p = 0.004). The median number of doses given was 3 (range 1-34). Median treatment duration was 5.0 weeks (range 0-77). Overall, 25.4% of patients experienced TRAEs and 4.8% experienced grade ≥3 TRAEs. The most common TRAEs were skin-related (13.1%) and constitutional symptoms (6.6%). Conclusions: Nivolumab/pembrolizumab had acceptable safety in CPB/C patients with aHCC. CP7, absence of diuretic-refractory ascites and lack of PV thrombosis were associated with better survival.

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Phase 2A Study of Copanlisib, a Novel PI3K Inhibitor, in Patients with Indolent Lymphoma

Blood ◽

10.1182/blood.v124.21.1701.1701 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1701-1701 ◽

Cited By ~ 7

Author(s):

Martin Dreyling ◽

David Cunningham ◽

Krimo Bouabdallah ◽

Sarit Assouline ◽

Eric Van den Neste ◽

...

Keyword(s):

Exploratory Study ◽

Research Funding ◽

Single Agent ◽

Objective Response ◽

Median Number ◽

Lymphocytic Leukemia ◽

Pi3k Inhibitor ◽

Aggressive Lymphoma ◽

Heavily Pretreated ◽

Grade 3

Abstract Background: Copanlisib is a novel pan-Class I phosphatidylinositol-3-kinase (PI3K) inhibitor with potent preclinical inhibitory activity against both PI3K-d and PI3K-α isoforms. Preliminary results from a phase II study of copanlisib in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) have been reported (Dreyling et al., ASH 2013), with an expansion cohort for patients with aggressive lymphoma still ongoing. We report here the final results of this exploratory study for patients with indolent NHL or CLL treated with copanlisib. Methods: Patients with histologically confirmed indolent NHL or CLL and relapsed or refractory to ≥2 prior lines of treatment were eligible. Copanlisib was administered at a dose of 0.8 mg/kg as a 1 hour intravenous infusion on days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as assessed per independent radiologic review according to the response criteria for lymphoma (Cheson et al., JCO 17:1244,1999) or the guidelines for diagnosis and treatment of CLL (Hallek et al., Blood 111:5446-56, 2008). Secondary endpoints included progression-free survival (PFS) and duration of response (DOR), safety and tolerability. Results: A total of 33 patients were treated in the indolent group, including: follicular NHL (FL) = 16, CLL = 13, marginal zone lymphoma (MZL) = 3, and small lymphocytic lymphoma (SLL) = 1. Median age was 68 years (range 46-89), M/F= 15/18. The median number of previous lines of treatment was 4. Thirty patients (91%) were previously exposed to rituximab. The median number of cycles received was 5.7 (mean 7.2); the median dose and median cumulative dosage of copanlisib administered were 52 mg (87% of planned dose) and 687 mg, respectively. Five patients were dose reduced to 0.6 mg/kg and 1 to 0.4 mg/kg. The ORR as determined by independent radiologic review in 32 evaluable patients was 47%, with 1 CR, 1 uCR, and 13 PRs. By histology, there were 1 CR, 1 uCR and 5 PRs for patients with FL (ORR 47%), and 2/3 PRs for patients with MZL and 1/1 PR for the patient with SLL, for an overall ORR for patients with indolent NHL (excluding CLL) of 53%. The ORR for patients with CLL was 38% (all PRs). Overall, the median DOR was 287 days (95% CI: 56; not yet reached); median PFS was 240 days (95% CI: 173; 419). The most common adverse events (AEs) of all grades were hyperglycemia (70%), hypertension (70%), fatigue (64%), diarrhea (36%), neutropenia (36%) and anemia (33%). Grade 3-4 AEs occurring in >10% of patients included: hypertension (49% grade 3), neutropenia (30%), hyperglycemia (30% grade 3), and anemia (15%). Dose reductions, interruptions, or permanent discontinuations due to AEs were reported in 4 (12%), 21 64%), and 11 (33%) patients, respectively. There was one drug-related grade-5 event; meningitis in a heavily-pretreated CLL patient with longstanding disease-related immunodeficiency, occurring shortly after first administration of copanlisib. Conclusions: Copanlisib is active as a single-agent in heavily pretreated, advanced refractory/relapsed FL, MZL, SLL, and CLL. Copanlisib exhibited an acceptable toxicity profile, consistent with previous reports. Based on the results of this exploratory study, a phase 2B study of copanlisib in relapsed or refractory indolent NHL (after prior treatment with an alkylating agent and rituximab) has been initiated and is ongoing. Disclosures Dreyling: Bayer HealthCare: Scientific advisory board/consultant Other. Cunningham:Roche: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Merck Serono: Research Funding; Novartis: Research Funding; Astra Zeneca: Research Funding. Giurescu:Bayer Pharma AG: Employment. Mappa:Bayer S.p.A.: Employment. Grunert:Bayer Pharma AG: Employment. Childs:Bayer HealthCare Pharmaceuticals: Employment.

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Phase II Trial of Irinotecan in Children With Relapsed or Refractory Rhabdomyosarcoma: A Joint Study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group

Journal of Clinical Oncology ◽

10.1200/jco.2006.06.1960 ◽

2007 ◽

Vol 25 (4) ◽

pp. 356-361 ◽

Cited By ~ 46

Author(s):

Gilles Vassal ◽

Dominique Couanet ◽

Elizabeth Stockdale ◽

Anne Geoffray ◽

Birgit Geoerger ◽

...

Keyword(s):

Phase Ii ◽

Response Rate ◽

Single Agent ◽

Objective Response ◽

Median Number ◽

Tumor Burden ◽

French Society ◽

Heavily Pretreated ◽

Grade 3 ◽

Multiagent Chemotherapy

PurposeThis phase II study was designed to evaluate the efficacy of irinotecan administered intravenously once every 3 weeks in pediatric patients with recurrent or refractory rhabdomyosarcoma.Patients and MethodsA total of 35 patients younger than age 20 years, with refractory or relapsed rhabdomyosarcoma for which standard treatments have failed, received irinotecan at 600 mg/m2administered as a 60-minute infusion every 3 weeks. Concomitant treatments included atropine for cholinergic symptoms, loperamide for diarrhea at the first liquid stool, and preventive antiemetic treatment. Tumor response was assessed every two cycles until progression according to WHO criteria.ResultsThe best overall response rate to irinotecan was 11.4% (95% CI, 3.2 to 26.7%; 2.9% complete responses, 8.5% partial responses) from all patients recruited. The median times to progression and survival were 1.4 and 5.8 months, respectively. A total of 112 cycles were administered, with a median number of two cycles per patient (range, 1 to 16). The most common grade 3/4 toxicities were neutropenia (46%), abdominal pain or cramping (17%), cholinergic syndrome (14%), nausea/vomiting (11%), anemia (11%), thrombocytopenia (9%), and diarrhea (6%).ConclusionIn heavily pretreated children with a high tumor burden who have been treated with multiagent chemotherapy, irinotecan administered intravenously as a single agent, at 600 mg/m2every 3 weeks, showed an interesting objective response rate and a good tolerance profile in rhabdomyosarcoma.

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Phase II study of 2-methoxyestradiol NanoCrystal dispersion (2ME2) alone and in combination with sunitinib (SU) in patients with metastatic renal cell carcinoma (mRCC) progressing on SU

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e16116 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e16116-e16116

Author(s):

M. R. Harrison ◽

R. Pili ◽

T. Logan ◽

G. Wilding ◽

J. Eickhoff ◽

...

Keyword(s):

Disease Progression ◽

Metabolic Response ◽

Single Agent ◽

Objective Response ◽

Median Number ◽

Clinical Activity ◽

Combination Strategies ◽

Rational Combination ◽

Grade 3 ◽

Number Of Cycles

e16116 Background: Panzem NCD (2ME2) is a non-estrogenic derivative of estradiol with antiproliferative and antiangiogenic activity that downregulates HIF-1α. One mechanism of VEGFR TKI failure may be upregulation of HIF-1α. We hypothesized that 2ME2 may have single-agent activity in pts who previously progressed on SU and that addition of 2ME2 may restore response in pts progressing on SU. Methods: Pts with clear cell mRCC who had previously received or were currently receiving SU with disease progression were eligible. Pts who had previously received SU were treated with 2ME2 alone (arm A). Pts currently on SU continued on the 4:2 schedule, with the addition of 2ME2 (arm B). All pts received 2ME2 at 1,500 mg PO TID, repeated in 6 wk cycles. The primary endpoint was objective response (OR) rate by RECIST. An exploratory endpoint was metabolic response on FDG-PET. Simon optimal 2-stage design was used with plans to enroll 21 pts/arm, and if activity was seen to continue enrollment for a total of 41 pts/arm. Results: 17 pts were enrolled (A: 10; B: 7). Median number of cycles on study was 1 (range <1 to 5). A pt remains on study in cycle 8. Adverse events (AE) of grade 3 or greater occurred in 4 pts (29%). Most frequent AE were: fatigue (71%), diarrhea (50%), dysgeusia (29%), anemia or decreased hemoglobin (29%), and anorexia (21%). Reasons for treatment discontinuation include: disease progression (7), pt/doctor discretion (3), AE (3), and noncompliance (1). No ORs by RECIST were seen. Conclusions: 2ME2 appears to have some single-agent activity, with an MR in a pt removed from study due to AE and a metabolic PR (ΔSUVmax -84%) in a pt with SD by RECIST. With 6/17 pts discontinuing therapy before meeting any OR endpoint, 2ME2 was not tolerable in this population. The study was closed to accrual knowing that a more promising 2ME2 analog is currently under development for oncologic use. The rationale to target HIF-1α after (and during) SU therapy remains of interest. This study design provides a unique way to assess both single-agent and rational combination strategies in pts with mRCC and should be utilized with other agents to seek evidence for clinical activity. [Table: see text]

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Tolerability and durable respones of the PI3Kδ inhibitor ME-401 administered on an intermittent schedule in relapsed/refractory (R/R) follicular lymphoma (FL) and other B-cell malignancies.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.8016 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 8016-8016

Author(s):

Andrew David Zelenetz ◽

Nishitha Reddy ◽

Deepa Jagadeesh ◽

Anastasios Stathis ◽

Huda S. Salman ◽

...

Keyword(s):

B Cell ◽

Single Agent ◽

Objective Response ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Combination Group ◽

Intermittent Schedule ◽

B Cell Malignancies ◽

Days Of Therapy ◽

Grade 3

8016 Background: ME-401, a potent, selective, and structurally differentiated oral PI3kδ inhibitor was evaluated in a dose escalation/expansion Phase 1b study, and previously demonstrated a high objective response rate (ORR) in FL and chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) when given on a continuous (CS) or an intermittent schedule (IS). IS appeared to significantly reduce the incidence of immune-mediated adverse events of special interest (AESI) associated with PI3kδ inhibitors (diarrhea, rash, transaminase elevation, pneumonitis). We report maturing data from patients treated on the IS in this study. Methods: Eligible patients (pts) had FL, CLL/SLL, marginal zone lymphoma (MZL) and diffuse large B-cell lymphoma (DLBCL), at least 1 prior therapy, adequate bone marrow and organs function, ECOG status ≤2, and no prior PI3K therapy. IS dosing: ME-401 at 60 mg/day for two 28-day cycles, followed by 7 days of therapy every 28-day cycle until disease progression or intolerance. Pts received ME-401 monotherapy (n = 21) or a combination with rituximab (n = 36) given at 375 mg/m2 for 8 doses in Cycles 1-6. Results: Total of 57 pts treated with IS: 35 FL, 10 CLL/SLL, 4 MZL, and 8 DLBCL with 38 (67%) currently still ongoing. Median age: 66 years (range 38-94) and median prior therapies: 2 (range 1-8). As of January 2020, median follow-up = 9.7 mo (range 0.6-25.4+). Grade 3 AESI reported in 7 pts: 2 diarrhea (3.5%), 2 colitis (3.5%), 1 rash (2%), 1 ALT increased (2%), and 1 pneumonitis (2%). No Grade 3 AESI reported beyond Cycle 3. Discontinuation for AE in 3 pts (5%). There were no discernable safety differences between the monotherapy and rituximab combination groups. ORR was 83% in FL (76% in monotherapy group, 88% in combination group) and 89 % in CLL/SLL (100%, 83%), with median duration of response not reached. Median PFS was not reached in all patients with FL and CLL (combined analysis of both single agent and with rituximab). ORR was 100% (4/4) in MZL and 25 % (2/8) in DLBCL (in combination group only). Conclusions: ME-401 administered on an IS was well-tolerated, with a low-rate of Grade 3 class-related AESI and achieved a high-rate of durable objective responses in R/R indolent B-cell malignancies. These results may differentiate ME-401 and support further evaluation as a single-agent and in combination regimens. An ongoing global trial is evaluating ME-401 by IS in pts with FL after failure of ≥2 prior therapies (NCT03768505). Clinical trial information: NCT02914938 .

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Phase 2 Study of Three Doses of Single Agent Bortezomib in Patients with Fludarabine-Refractory B-Cell CLL.

Blood ◽

10.1182/blood.v104.11.4841.4841 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4841-4841

Author(s):

Stefan Faderl ◽

Kanti R. Rai ◽

John Gribben ◽

Ian Flinn ◽

John C. Byrd ◽

...

Keyword(s):

B Cell ◽

Apoptotic Cell ◽

Control Cell ◽

Single Agent ◽

Proteasome Inhibition ◽

Median Number ◽

Clinical Activity ◽

Tumor Spread ◽

Proteasome Pathway ◽

Grade 3

Abstract Bortezomib (formerly PS-341, VELCADE®) is a selective inhibitor of the ubiquitin-proteasome pathway, which plays an important role in degrading regulatory proteins that control cell cycle functions, neoplastic growth and tumor spread. It has been approved by the FDA for the treatment of relapsed and refractory myeloma patients (pts). Phase I and II trials have suggested activity in B-cell indolent and aggressive lymphomas including mantle cell lymphoma. Preclinical studies have also shown that B-CLL cells undergo apoptotic cell death following inhibition of the proteasome pathway. We therefore conducted a multicenter phase II study to assess the safety and efficacy of 3 doses of bortezomib in pts with B cell CLL who were refractory to or intolerant to fludarabine. Pts with an ANC ≥ 1 x 109/L and platelets ≥ 30 x 109/L were eligible. Bortezomib was given as i.v. push on days 1, 4, 8, and 11 of a 21 day course for a maximum of 9 courses. Pts were initially randomized to 1.0 (n=5) versus 1.3mg/m2/dose (n=9) and later, after review of preliminary data, to 1.3 versus 1.5mg/m2/dose (n=8). Twenty-two pts were enrolled. Median age 62 yrs (range 46-83). Median number of prior therapies 4 (2–11). Median number of yrs from diagnosis to therapy 5.5 (0.8–14.2). b2-microglobulin > 5.5 mg/L in 10 pts (45%). Fifteen pts (68%) had ≥ Rai stage 3. Of 19 evaluable pts no responses according to NCIWG criteria were demonstrated [stable disease 8 pts (42%), progressive disease 11 pts (58%)] based on investigator assessment. When analyzed by specific sites of disease, five pts (23%) experienced ≥ 50% decrease in ALC and 6 pts (27%) showed ≥ 50% decrease in lymphadenopathy. Bortezomib was well tolerated throughout all 3 dosing groups. Most common toxicities were ≤ grade 2 and included nausea (n=9;42%), headache (6;27%), diarrhea (5;23%), vomiting (5;23%), dyspnea (5;23%), anorexia (5;23%), and peripheral neuropathy (3;14%/ grade 3 in 1 pt). Pharmacodynamic evaluation of 20S proteasome inhibition at 1 hour postdose was similar to that reported for these doses in other studies, and was highest in the 1.5mg/m2 dosing group. We conclude that bortezomib as single agent is not effective in pts with fludarabine-refractory B-cell CLL at these doses. However, in view of the evidence of clinical activity, further exploration of bortezomib in combination with other agents might be the appropriate next step to define the optimal role of this new agent in the management of advanced CLL.

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Phase II trial of nanoparticle albumin-bound paclitaxel (ABX) + capecitabine (XEL) in first line treatment of metastatic breast cancer (MBC)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.10731 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 10731-10731

Author(s):

D. Mintzer ◽

L. S. Schwartzberg ◽

P. Cobb ◽

D. Henry ◽

A. Epperson ◽

...

Keyword(s):

Phase Ii ◽

Response Rate ◽

Single Agent ◽

Objective Response ◽

Metastatic Breast ◽

Dose Intensity ◽

Open Label ◽

Improve Response Rate ◽

Safety And Efficacy ◽

Grade 3

10731 Background: ABX and XEL both have substantial single agent activity in MBC. Taxane and anti-metabolic doublets improve response rate and TTP compared to singlet therapy. ABX given weekly has excellent safety and efficacy profile with maintenance of dose intensity. We designed this study to test the safety and efficacy of ABX + XEL given in a novel combination schedule. Methods: This phase II, multicenter open label study utilized ABX 125 mg/m2 IV on day 1, 8 and with no premeds and Xeloda 825 mg/m2 PO days 1–14 every three weeks. Entry criteria include measurable MBC by RECIST, no prior chemo for metastatic disease, > 6 months since adjuvant fluoropyrimidine and paclitaxel. A total of 50 patients (pts) are scheduled to be enrolled. Primary endpoint is objective response rate. Results: To date, 14 patients have entered on study. Safety analysis prespecified by the protocol is completed in the 1st six patients. No unique, unexpected or grade 4 toxicities have occurred. Two patients have grade 3 hand-foot syndrome, one had grade 3 neutropenia and one had grade 3 fatigue. Enrollment is continuing without change in dose/schedule. Response data is available in the first two cycles of therapy in 8 patients. At this point, two pts have achieved PR, four have stable disease and two have progressive disease. Conclusions: The combination of weekly ABX plus daily XEL orally at clinically effective doses is safe and shows preliminary evidence of efficacy. Complete enrollment of this trial is expected by May 2006 and updated results will be presented. [Table: see text]

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LR-CD: Efficacy of Combination Therapy with Lenalidomide for Untreated Indolent B-Cell NHL.

Blood ◽

10.1182/blood.v120.21.2741.2741 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2741-2741

Author(s):

Craig Reeder ◽

Stephen M Ansell ◽

Katherine Gano ◽

Amylou C. Dueck ◽

Christopher Conley ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

Single Agent ◽

Stage Iv ◽

B Cell Lymphoma ◽

Patient Characteristics ◽

Response Rates ◽

Median Number ◽

Non Hodgkin Lymphoma ◽

Grade 3

Abstract Abstract 2741 Background: The novel agent lenalidomide (LEN) has shown significant single-agent activity in patients with relapsed lymphoma through anti-proliferative and immunomodulatory mechanisms. In combination LEN may synergistically improve the efficacy of rituximab. However, there is limited data on the efficacy and safety of LEN in multi-drug combination regimens for treatment-naïve patients. We designed a phase II single arm trial to evaluate tumor response, toxicity (AE) and survival with a combination of LEN, rituximab, cyclophosphamide (CTX) and dexamethasone (DEX) (LR-CD) in symptomatic untreated patients with indolent B-cell lymphoma. (NCT00784927). Methods: Eligibility required age ≥18, ECOG PS ≤2, confirmed diagnosis of indolent B-cell lymphoma (FL1–2, SLL, MZL or LPL/WM), measurable nodes ≥2cm or IgM ≥400mg/dL (LPL/WM), ANC ≥1400/mm3, platelets ≥100,000/mm3, creatinine ≤2mg/dL, and signed informed consent. Only patients needing therapy were considered eligible. Treatment consisted of IV rituximab 375mg/m2 D1, oral LEN 20mg D1–21, CTX 250mg/m2 D1, 8, 15, DEX 40mg D1, 8, 15, 22 and ASA 325 mg daily in a 28 day cycle. Treatment continued 2 cycles beyond best response up to a maximum of 12 cycles. Toxicity was assessed by NCI CTCAE v3.0. Results: Thirty-one patients have enrolled at Mayo Clinic with 28 evaluable for toxicity and response (1 deemed ineligible, 1 withdrew before treatment, 1 treatment violation). Four patients continue on study at this time. Patient characteristics: median age 68.5(43–83), 71% male, stage IV 86%, FL 28%, MZL 25%, LPL/WM 39%, and SLL 4%. Median number of cycles given was 6 and 71% completed the study per protocol. The best overall response is 89% with 32% CR and 57% PR. In subgroup analysis, the response rates for LPL/WM was 91% (all PR) and for FL 88% (CR 63%, PR 25%). The most common grade ≥3 AEs were neutropenia (35.7%), leukopenia (17.8%), anemia (14.3%) and thrombosis (14.3%). The LPL/WM subgroup experienced more grade ≥3 anemia (36%) compared to the group as a whole. Patients (57%) required at least one dose reduction of LEN (n =10), CTX (n = 9) or DEX (n = 7). At a median f/u of 14.5 (1.8–36.5) months 86% are progression free (fig. 1) and the OS is 96% (fig. 2). One death unrelated to treatment occurred 7.7 months after completing 12 cycles of treatment. Conclusion: Lenalidomide can be safely combined with other active agents and in the combination LR-CD produces high response rates in symptomatic patients with indolent B-cell lymphoma. The regimen is well tolerated with manageable toxicities which are similar to that seen with single agent LEN. The encouraging results seen in patients with LPL/WM have led to expansion of this cohort for additional study. Disclosures: Reeder: Celgene: Research Funding. Off Label Use: lenalidomide use in non-Hodgkin lymphoma. Stewart:Celgene: Consultancy, Honoraria.

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Belinostat in combination with standard cyclophosphamide, doxorubicin, vincristine and prednisone as first-line treatment for patients with newly diagnosed peripheral T-cell lymphoma

Experimental Hematology and Oncology ◽

10.1186/s40164-021-00203-8 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Patrick B. Johnston ◽

Amanda F. Cashen ◽

Petros G. Nikolinakos ◽

Anne W. Beaven ◽

Stefan Klaus Barta ◽

...

Keyword(s):

T Cell ◽

Cell Lymphoma ◽

Single Agent ◽

Dose Intensity ◽

Maximum Tolerated Dose ◽

Primary Objective ◽

T Cell Lymphoma ◽

Hematologic Toxicity ◽

Peripheral T Cell Lymphoma ◽

Grade 3

Abstract Background Belinostat is a histone deacetylase inhibitor approved for relapsed refractory peripheral T-cell lymphoma (PTCL). The primary objective of this study was to determine the maximum tolerated dose (MTD) of belinostat combined with CHOP (Bel-CHOP). Secondary objectives included safety/tolerability, overall response rate (ORR), and belinostat pharmacokinetics (PK). Methods Patients were ≥ 18 years with histologically confirmed, previously untreated PTCL. Patients received belinostat (1000 mg/m2 once daily) + standard CHOP for 6 cycles with varying schedules using a 3 + 3 design in Part A. Part B enrolled patients at MTD dose. Results Twenty-three patients were treated. One patient experienced DLT (Grade 3 non-hematologic toxicity) on Day 1–3 schedule, resulting in escalation to Day 1–5 schedule (n = 3). No DLTs were observed and Day 1–5 schedule with 1000 mg/m2 was declared as MTD. Twelve additional patients were enrolled in Part B using MTD. Median relative dose intensity was 98%. All patients experienced adverse events (AEs), including nausea (78%), fatigue (61%), and vomiting (57%). Serious AEs occurred in 43%, with febrile neutropenia (17%) and pyrexia (13%). Overall ORR was 86% with 71% reported CR at MTD. Belinostat PK parameters were similar to single-agent. Conclusions Bel-CHOP was well tolerated and MTD in CHOP combination was the same dose and schedule as single agent dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT01839097.

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Phase 1/2 study of cirmtuzumab and ibrutinib in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.7556 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 7556-7556

Author(s):

Hun Ju Lee ◽

Michael Y. Choi ◽

Tanya Siddiqi ◽

Jacqueline Claudia Barrientos ◽

William G. Wierda ◽

...

Keyword(s):

Phase 1 ◽

Single Agent ◽

Objective Response ◽

Median Number ◽

Lymphocytic Leukemia ◽

Synergistic Activity ◽

Best Response ◽

Car T ◽

Treatment Naïve

7556 Background: Cirmtuzumab (Cirm) is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and had demonstrated additive/synergistic activity with many anti-cancer agents including ibrutinib (Ibr). Methods: Patients (Pts) with relapsed or refractory (RR) MCL or treatment naïve (TN) or RR CLL were enrolled. In Part 1 (Dose Escalation), doses of Cirm IV q2wks x5 then q4wks of 2-16 mg/kg and 300 or 600 mg were examined. Safety of Cirm alone was assessed during the first 28 days, then Ibr was started at approved doses for each indication. Cirm 600 mg IV q2wks x3 then q4wks in combination with Ibr starting day 0 was chosen as the recommended dosing regimen for use in Part 2 (Expansion) and Part 3 (CLL only, Cirm/Ibr vs. Ibr alone). Results: Twelve evaluable MCL pts were enrolled into Part 1, and 5 into Part 2. Median number of prior regimens was 2 (1-5), including pts relapsing after Ibr (4), auto-SCT (3), auto-SCT/ allo-SCT (1), auto-SCT/CAR-T (1). In CLL, 34 evaluable pts (12 TN and 22 RR) enrolled into Part 1 (18) or Part 2 (16). At least 74% of CLL pts in Parts 1 and 2 were high risk as determined by unmutated IGHV, del17p, and/or del11q. In Part 3, 22 evaluable pts received Cirm/Ibr (15) or Ibr (7). As of the 30OCT2020 safety cut-off for MCL and CLL, common TEAEs (all grades) included diarrhea (41%), contusion (39%), fatigue (39%), URI (31%), hypertension (25%) arthralgia (23%). Grade ≥3 neutropenia was 13% and thrombocytopenia 1%. There were no Cirm dose reductions or discontinuations for toxicity. Overall, Cirm did not appear to negatively impact the safety of Ibr. Efficacy (MCL): As of the 02FEB2021 efficacy cutoff, the best response of 17 evaluable pts in Parts 1 and 2 included an objective response rate (ORR) of 82%, 41% CR/CMR, 41% PR, 12% SD, and 6% PD. CR/CMR remain durable from 8-28+ mos. Most responses occurred rapidly after ̃3 mos of Cirm/Ibr. Notably, responses were achieved in all pts who received prior SCT+/- CAR-T (4CR, 1PR) or prior Ibr (2CR, 2PR). At a median follow-up of 14.6 mos, the median PFS (mPFS) had not been reached (NR) (95% CI: 17.5, NA). Efficacy (CLL): The best response of 34 evaluable pts in Parts 1 and 2 included 91% ORR, 3% CR, 88% PR/PR-L, 9% SD, 0% PD. In Part 3, both arms achieved 100% ORR (all PRs). At a median follow-up of 20.2 mos, the mPFS was NR (95% CI: NA, NA), and the PFS estimate at 24 months was 95% for R/R, and 87% for TN, respectively, for evaluable CLL pts receiving Cirm/Ibr. Conclusions: Cirm/Ibr is a well-tolerated, active regimen in both MCL and CLL. For MCL, the mPFS of NR (95% CI: 17.5, NA) and CRR (41%), with all CRs remaining without PD, compare favorably to mPFS of 12.8 mos (95% CI 8.5-16.6) and CRR (20%) reported for single agent Ibr (Rule 2017). For CLL, the high ORR and PFS are encouraging, particularly for RR CLL. The study is ongoing, with MCL enrollment expanded to study Cirm + Ibr in pts who have had a suboptimal response to an Ibr regimen, or who have failed other approved BTKi agents. Clinical trial information: NCT03088878.

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