Preliminary Safety and Efficacy of the Combination of Brentuximab Vedotin and Ipilimumab in Relapsed/Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4412)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 585-585 ◽  
Author(s):  
Catherine S. Diefenbach ◽  
Fangxin Hong ◽  
Jonathon B. Cohen ◽  
Michael J. Robertson ◽  
Richard F. Ambinder ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Checkpoint Inhibitor ◽  
Sensory Neuropathy ◽  
Peripheral Sensory Neuropathy ◽  
Level 1 ◽  
Grade 3 ◽  
Peripheral Sensory ◽  
Level 2

Abstract Background: Despite advances in chemotherapy, R/R HL remains a significant clinical problem with over 1,000 primarily young lives lost annually. HL is a unique tumor in which a small number of malignant Hodgkin Reed-Sternberg (HRS) cells propagate an immunosuppressive microenvironment that augments HRS growth and survival. We hypothesized that immune checkpoint inhibitor therapy could activate the tumor immune microenvironment, while the CD30 expressing HRS cells could be targeted by brentuximab vedotin (BV), thereby overcoming tumor cell resistance and deepening clinical responses. E4412 is a phase 1 ECOG-ACRIN sponsored study of the combination of BV and the checkpoint inhibitors ipilimumab (IPI) and nivolumab (NIVO) in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL). Here we report the data on the patients treated with BV + IPI, the first cohort of the study. Methods: Patients with biopsy proven R/R HL were treated with BV 1.8mg/kg and two escalating doses of IPI: 1 mg/kg or 3mg/kg. After safety was determined an expanded cohort was treated with BV 1.8mg/kg IV and IPI 3mg/kg IV. The schedule consisted of BV administered every 21 days for 16 cycles and IPI every 21 days x 4 doses and thereafter every 3 months for up to a year. Dose limiting toxicity (DLT) was defined for purposes of dose escalation within the first cycle of therapy. Patients are followed for toxicity up to 30 days beyond their last treatment. Results: As of 7/2015 19 of 23 planned patients have been treated with BV + IPI. We report the data on the full dose escalation population (13 patients: Dose level 1 (6), Dose level 2 (7)). The median age was 33 years (range: 20-49). Seven patients were male. Patients were heavily pretreated with a median of 4 prior therapies (2-13). Fourpatients had prior treatment with BV; 8 patients had prior SCT (7 autologous, 1 allogeneic). Safety: Overall the regimen of BV + IPI was extremely well tolerated with no DLTs noted during dose escalation. Toxicities considered at least possibly related to drug during any cycle of treatment are shown according to grade in Table 1. The most common treatment related adverse events were: diarrhea, rash, and peripheral sensory neuropathy. Other AEs of interest included: alopecia, transaminitis, and uveitis. Grade 3 and 4 treatment related adverse events (AEs) included: Dose level 1: one grade 3 infusion reaction, which led to a protocol amendment to include premedication, no further grade 3 infusion reactions were noted; Dose level 2: one each: grade 3 rash, vomiting, and peripheral sensory neuropathy, and one grade 4 thrombocytopenia in patient with pre-existing thrombocytopenia. Response: For the 12 evaluable patients, the overall response (ORR) for the combination of BV + IPI was 67% with a complete response (CR) rate of 42% (5 of 12 patients). An additional 2 patients had stable disease (SD) giving a clinical benefit rate of 83%. Three of 5 of the CRs occurred at dose level 1 (1mg dose of IPI). The median progression free survival (PFS) is 0.74 years with a median follow-up of 0.66 years. Conclusion: In this first reported study of the combination of checkpoint inhibitor and ADC, toxicity was low, primarily grades 1 and 2. In a heavily pretreated patient population, 33% of whom had had prior BV and 67% of whom were s/p ASCT, the ORR of 67% and CR rate of 42% suggests a potential deepening of response compared to monotherapy. More than half of these CRs occurred at 1mg of IPI suggesting that in combination with ADC, low doses of immune stimulation may be highly active. Optimization of this combination strategy is planned with ongoing accrual to cohorts receiving BV + NIVO, and BV + IPI + NIVO. Data will be updated to include the full BV + IPI cohort by the time of the annual meeting. Table 1. Common and Immune Toxicities Toxicity Type Dose Level 1 (n=6) Dose Level 2 (n=7) Grade Grade 1,2 3 4 5 1,2 3 4 5 (n) (n) (n) (n) (n) (n) (n) (n) Fatigue 5 - - - 3 - - - Fever 1 - - - 3 - - - Pain 2 - - - 3 - - - Alopecia 2 - - - 1 - - - Pruritus 1 - - - 2 - - - Rash maculo-papular 4 - - - 2 1 - - Diarrhea 4 - - - 4 - - - Dyspepsia 2 - - - 1 - - - Nausea 6 - - - 4 - - - Vomiting 3 - - - 2 1 - - Papulopustular rash 1 - - - 1 - - - Alanine aminotransferase increased 3 - - - 3 - - - Aspartate aminotransferase increased 3 - - - 2 - - - Platelet count decreased - - - - - - 1 - Anorexia 3 - - - - - - - Headache 2 - - - 2 - - - Peripheral sensory neuropathy 5 - - - 4 1 - - Dry eye 2 - - - - - - - Uveitis 1 - - - - - - - Cough 2 - - - 1 - - - Disclosures Diefenbach: Molecular Templates: Research Funding; Immunogen: Consultancy; Celgene: Consultancy; Idera: Consultancy; Jannsen Oncology: Consultancy; Gilead: Equity Ownership, Research Funding, Speakers Bureau; Incyte: Research Funding; Genentech: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Off Label Use: Presentation will discuss the experimental use of the checkpoint inhibitor Ipilimumab in relapsed/refractory Hodgkin lymphoma.. Cohen:Celgene: Consultancy; Millennium: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; BMS: Research Funding; Janssen: Research Funding. Robertson:Eli Lilly: Equity Ownership. Fenske:Pharmacyclics: Honoraria; Seattle Genetics: Honoraria; Millennium/Takeda: Research Funding; Celgene: Honoraria. Kahl:Roche/Genentech: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy; Cell Therapeutics: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.

Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy Induces High Response Rates in Agressive Chronic Lymphocytic Leukemia (CLL) and Richter's Syndrome (RS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3443-3443 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
William Wierda ◽  
William Plunkett ◽  
Susan O'Brien ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rates ◽  
Off Label ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 3443 Poster Board III-331 Introduction The first Phase I-II clinical trial of oxaliplatin, fluradabine, cytarabine (Ara-C), and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate and decrease myelosuppression, the dose of oxaliplatin was increased to 30mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods In a Phase I-II study of OFAR2, patients were treated with oxaliplatin 30mg/m2, D1-4; fludarabine 30mg/m2, Ara-C 0.5g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg, D6. Fludarabine and Ara-C were given on D2-3 (dose level 1) D2-4 (dose level 2) or D2-5 (dose level 3); courses were repeated every 4 weeks. Patients received prophylaxis for tumor lysis, DNA viruses, and PCP. A “3+3” design was used and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results Ninety-one patients (CLL, 67; RS, 24) have been treated to date: Phase I, 12 patients (by dose level: 1, n=3; 2, n=6; and 3, n=3). DLTs were noted in 2 of 3 patients on dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1); thus, dose level 2 was the MTD. Seventy-nine patients (relapsed CLL, 58; RS, 19) have been treated in the Phase II portion of the study. Patient characteristics were as follows: age > 60 years, 65%; 17p deletion, 38%; 11q deletion, 13%; 13q deletion, 16%; trisomy 12, 21%; no findings, 12%; unmutated IgVH, 80%; ZAP70-positive, 75%; and CD38 ≥30%, 58%. Response in patients treated in the Phase II recommended dose is shown in Table (evaluable, 67). The overall response rates in patients with 17p and 11q deletions were 48% and 55%, respectively. The median survival duration was 21 months (CLL, 21 months; RS, 9.5 months). At 18 months, the survival rates in patients with 17p and 11q deletions were 66% and 76%, respectively. Twelve patients underwent stem cell transplantation after OFAR2 (as post-remission therapy, n=10; as salvage, n=2). Overall, 196 cycles were administered. Grade 3-4 neutropenia, thrombocytopenia, and anemia were noted in 63%, 72%, and 39% of patients and in 57%, 70%, and 25% of cycles and Grade 3-4 infections in 19% of patients. Conclusion Preliminary results demonstrated that OFAR2 induced response in 40% of patients with RS and 63% of patients with relapsed/refractory CLL. OFAR2 had antileukemic activity in patients with 17p deletion. Clinical outcomes appeared to be superior to those of OFAR1 in refractory CLL, whereas results of OFAR1 appeared to be superior to those of OFAR2 in RS. Accrual is ongoing. Disclosures Tsimberidou: ASCO: ASCO Career Development Award; Sanofi: Research Funding. Off Label Use: Oxaliplatin is used off-label. Wierda:Genentech: Honoraria; Bayer, Sanofi-Aventis, Abbott, GSK: Research Funding; GSK, Trubion, Ligand, Genentech, Medimmune, Abbot: Consultancy; Celgene: Speakers Bureau. Plunkett:Sanofi-Aventis: Research Funding. O'Brien:Genentech: Research Funding; Sanofi: Consultancy. Kipps:NCI: Grant P01CA-81534.

scholarly journals A Pilot Study of CPX-351 (Vyxeos ©) for Transplant Eligible, Higher Risk Patients with Myelodysplastic Syndrome

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 540-540
Author(s):  
Meagan A. Jacoby ◽  
David A. Sallman ◽  
Bart L. Scott ◽  
Megan Haney ◽  
Fei Wan ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Induction Dose ◽  
Level 1 ◽  
Level 2 ◽  
Very High

Abstract Introduction: CPX-351 (Vyxeos ©; daunorubicin and cytarabine liposome for injection) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar drug ratio that is FDA approved for treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Secondary AML is clinically and biologically similar to MDS, sharing many of the same genetic mutations. We hypothesize that CPX-351 therapy may result in deeper responses than traditional therapy with hypomethylating agents, with acceptable tolerability, and translate into better outcomes in the MDS population. This is a multicenter, dose-escalation and safety expansion study (NCT03572764) to investigate induction and consolidation therapy with CPX-351 in a transplant eligible, higher risk MDS population. Methods: Two dose levels were investigated in the dose-escalation portion. Induction Dose Level 1: (daunorubicin 29 mg/m 2 and 65 mg/m 2 cytarabine) liposome on days 1, 3, 5; and Induction Dose Level 2: (daunorubicin 44 mg/m 2 and 100 mg/m 2 cytarabine) liposome on Days 1, 3, 5. The primary objectives were to evaluate safety and to determine the dose-limiting toxicities (DLTs) and recommended Phase 2 dose (RP2D). DLTs were assessed during the induction period (up to day 56 to evaluate for prolonged myelosuppression). Additionally, a dose expansion (for up to 20 treated patients) was performed at the RP2D. After induction, patients could receive up to two cycles of consolidation per dose level: Dose Level 1, (daunorubicin 14.3 mg/m 2 and 32 mg/m 2 cytarabine) liposome on Days 1 and 3; or Dose Level 2 (daunorubicin 29 mg/m 2 and 65 mg/m 2 cytarabine) liposome on Days 1 and 3. After induction, the patient could proceed to alloHCT at any time at the discretion of the treating physician. Key eligibility criteria included MDS patients who were naïve to hypomethylating agents, aged 18-70 years, an IPSS-R score > 3 (Intermediate, High or Very High Risk), ≥ 5% bone marrow myeloblasts, and suitable candidates for cytotoxic induction therapy and allogeneic hematopoietic cell transplant (alloHCT). Key secondary endpoints were day 30 and 60 post-induction mortality, the proportion of patients proceeding to alloHCT, and response assessments per IWG 2006 criteria. Results: As of abstract submission, 19 patients have been treated and dose escalation is complete. The dose escalation portion included 12 patients (Dose Level 1, n=6; Dose Level 2, n=6), and the safety expansion to date includes 7 patients treated at Dose Level 2. The median age was 64 years (range, 18-68), 67% were female, and the IPSS-R risk categories were as follows: intermediate (n=1, 5%), high (n=10, 53%) and very high (n=8, 42%). There were no DLTs in either Dose Level 1 or Dose Level 2, and Dose Level 2 was selected for safety expansion. Treatment-emergent adverse events (TEAEs) were evaluated in the 18 patients who had completed induction (Table). The most common TEAEs were hematologic, as expected. The most common non-hematologic TEAEs were febrile neutropenia (n=13, 72.2%), hypertension (n=9, 50%), and sepsis (n=5, 27.8%). SAEs included febrile neutropenia (n=5), sepsis (n=2), lower GI hemorrhage (n=2, two instances in the same patient), atrial fibrillation (n=1), pneumonitis (n=1), and catheter related infection (n=1). To date, the 30 and 60 day mortality is 0% and 5% (n=1), respectively, with the 1 death unrelated to therapy and due to progression of disease to AML. Of the 19 patients, 13 have received alloHCT with 4 still potentially alloHCT candidates. Of response evaluable pts (n=18, 1 pt pending response evaluation at data cutoff), the overall response rate was 78% with best overall responses of CR (n=4), mCR (n=10), stable disease (n=2), progressive disease (n=2) and pending (n=1). Of the 10 patients with mCR, 3 also had hematologic improvements. Conclusions: CPX-351 (daunorubicin 44 mg/m 2 and 100 mg/m 2 cytarabine) liposome on Days 1, 3, 5, has demonstrated a tolerable safety and promising efficacy profile when used in a transplant eligible, higher risk MDS population, warranting further study. Updated safety and efficacy outcomes will be presented at the meeting. Figure 1 Figure 1. Disclosures Jacoby: Abbvie: Research Funding; Jazz: Research Funding. Sallman: Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Incyte: Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees. Scott: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Komrokji: AbbVie: Consultancy; Acceleron: Consultancy; Geron: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Uy: AbbVie: Consultancy; Macrogenics: Research Funding; Agios: Consultancy; GlaxoSmithKline: Consultancy; Novartis: Consultancy; Genentech: Consultancy; Astellas: Honoraria, Speakers Bureau; Jazz: Consultancy. OffLabel Disclosure: CPX-351 (Vyxeos©; daunorubicin and cytarabine liposome for injection) is FDA approved for treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes

High Response Rate of Romidepsin in Combination with ICE (Ifosfamide, Carboplatin and Etoposide) in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma: Updates of Phase I Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3987-3987 ◽  
Author(s):  
Dai Chihara ◽  
Yasuhiro Oki ◽  
Jason R Westin ◽  
Loretta Nastoupil ◽  
Luis E. Fayad ◽  
...  
Keyword(s):  
Dose Level ◽  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Median Number ◽  
Peripheral T Cell Lymphoma ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Background: Survival for patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) remains very poor. Outcomes for these patients may be improved by stem cell transplant particularly if in complete remission (CR) prior to transplant (Smith 2013). ICE (ifosfamide, carboplatin and etoposide) and romidepsin single agent are options for the treatment of relapsed/refractory PTCL; however, the CR rate of both treatments is less than 30% (Zelenetz 2003, Mikesch 2013, Coiffier 2012). With the goal of increasing CR rates pre-transplant, we conducted a phase I study of romidepsin in combination with ICE in patients with relapsed/refractory PTCL. Methods: The primary objective of this trial is to determine the toxicity profile and to identify the maximum tolerated dose (MTD) of the romidepsin in combination with standard ICE. Romidepsin was administered intravenously on days 1 and 4 of ICE, at 8mg/m2 (dose level 1), 10mg/m2 (level 2),or 12mg/m2 (level 3). All patients received pegfilgrastrim or filgrastrim for growth factor support. Patients could receive next cycle of treatment on day 14 if ANC was > 1 and platelets were ≥ 75,000 with ≥ 20,000 allowed if patients had bone marrow involvement with PTCL at time of enrollment. Dose escalation was conducted using a modified toxicity probability interval method (Ji 2010). Dose limiting toxicity (DLT) was defined as any grade 3 or 4 non-hematologic toxicity attributed to therapy that could not be controlled or prevented by supportive care or grade 4 thrombocytopenia or neutropenia that lasts for more than 14 days. Results: At the time of the data cut off (August 2015), a total of 17 patients were registered (6 PTCL-NOS, 7 AITL, 1 ALK+ALCL, 1 ALK-ALCL, 1 HSTL, 1 NK/TCL); 15 were evaluable for toxicity and 14 were assessable for response (Cheson 2007). Two, 12 and 1 patients were treated at dose level 1, 2 and 3, respectively. Since DLT with thrombocytopenia was seen in patient who received dose level 3, we continued enrollment in dose level 2. Median age of patients was 60 (range 24-70) years and 10 patients (67%) had primary refractory disease. Median number of prior regimens was 1 (range 1-2) and 1 patient had received a prior front-line consolidative ASCT. Overall, 37 cycles were given to the patients with a median number of treatment cycles of 2 (range 1-4). The median days to the next cycle was 21 days (range: 14-33). Common grade 1/2 non-hematologic toxicities included nausea (51%), vomiting (43%), fatigue (41%) and dyspnea (19%). Grade 3/4 thrombocytopenia, grade 3/4 neutropenia and grade 3 anemia occurred in 95%, 84% and 73% of the cycles; however, febrile neutropenia occurred only in 1 cycle. Dose limiting toxicities included renal failure in dose level 2 and persistent grade 4 thrombocytopenia in dose level 3, and these DLTs led to expansion of dose level 2. The overall response rate was 78% (11/14, 95%CI: 49-95%) with CR rate of 64% (9/14, 95%CI: 35-87%). Three patients each underwent allogeneic and autologous transplant, respectively. Among them, three patients (two after allogeneic and one after autologous transplant), experienced relapse. With censoring the patients at the date of transplant for the survival analysis, median progression-free survival is 10.0 months. Summary: In conclusion, romidepsin plus ICE is an effective salvage regimen but with a higher rate of hematologic toxicities. Despite a relatively high CR rate relapses do continue to occur indicating the need of improving consolidation or maintenance approaches. Treatment of a larger number of patients is underway to optimize the dose of romidepsin when combined with ICE. Disclosures Westin: Spectrum: Research Funding. Nastoupil:AbbVie: Research Funding; Genentech: Honoraria; Janssen: Research Funding; Celgene: Honoraria; TG Therapeutics: Research Funding. Fanale:Celgene: Honoraria.

scholarly journals Phase 1 Study of MDR1 Inhibitor Plus Brentuximab Vedotin in Relapsed/Refractory Hodgkin Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1636-1636 ◽  
Author(s):  
Robert W. Chen ◽  
Lu Chen ◽  
Alex F. Herrera ◽  
Matthew Mei ◽  
Katrina McBride ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Dose Level ◽  
Research Funding ◽  
Overall Response Rate ◽  
Brentuximab Vedotin ◽  
Overall Response ◽  
Duration Of Response ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Background: Brentuximab vedotin (BV), an antibody drug conjugate (ADC), selectively delivers anti-tubulin agent monomethyl auristatin E (MMAE) to CD 30+ cells. In a multi-center phase II trial in patients with relapsed/refractory Hodgkin lymphoma (HL), BV showed an overall response rate (ORR) of 75%, a complete response (CR) rate of 34%, and a median duration of response (DOR) of 6.7 months (Younes A et al, JCO 2012). Although this drug has high response rates in HL, many patients will eventually develop resistance. We have shown that resistance to BV is associated with upregulation of MDR1 (multidrug resistance pump), and BV resistance cells have a decreased intracellular concentration of MMAE as a result of overexpression of drug export pump (Chen et al, MCT 2015). Cyclosporine (CsA), an immunosuppressant, can inhibit drug export pump by competitive binding. It has been combined with non-targeted chemotherapy to overcome drug resistance in the past without significant benefits. However, it has never been combined with targeted therapies such as antibody drug conjugates. We found that addition of CsA to BV restores intracellular MMAE concentration in BV resistant cell lines and restores the IC50 to BV (Chen ASH 2017). In BV resistant mouse xenograft models, addition of CsA also restores BV sensitivity (Chen ASH 2017). We hypothesize that the combination of CsA and BV is safe and efficacious, thus we designed and conducted a phase I trial using the combination of CsA plus brentuximab vedotin in patients with R/R HL. Patients and Methods: This is a prospective, phase I trial with a 3 + 3 design in patients with relapsed/refractory HL. All patients had biopsy proven relapsed/refractory HL. Three dose levels are planned: 1) 1.2 mg/kg BV every 21 days and 5 mg/kg CsA PO BID on D 1-5, 2) 1.8 mg/kg BV every 21 days and 5 mg/kg CsA PO BID on D 1-5. 3) 1.8 mg/kg BV every 21 days and 7.5 mg/kg of CsA PO BID on D 1-5. DLT period is 21 days. Patients who were relapsed/refractory to BV were allowed. The primary endpoint was MTD. Secondary endpoints were safety, ORR, duration of response, and correlative analysis. Imaging studies were performed every two cycles with alternating CT and CT/PET scans. Response criteria were per Lugano 2014. Results: Thirteen patients were accrued, and all were evaluable for toxicity and 12/13 for efficacy. The baseline characteristics are shown in table 1 and include: previous BV (100%), previous PD1 inhibitor (92%), previous HCT (62%), male predominance (54%), Caucasian predominance (85%), median age of 37, stage III/IV (69%), refractory to previous BV (92%), progressed after PD1 blockade (92%). There was 0 DLT at dose level 1 (0/3), 1 DLT of abdominal pain (grade 3) and neutropenia at dose level 2 in the same patient (1/6 patients), and 4 DLT in 2 out of 3 patients treated at dose level 3. The DLTs were grade 3 hyperglycemia (1), grade 3 bone pain (1), grade 3 constipation (1), and grade 4 lymphopenia (1). Thus dose level 2 is the MTD. Grade 3 or higher possibly-related toxicities (excluding DLT) included neturopenia (6) anemia (4), lymphopenia (3), hyponatremia (3), hypophosphatemia (3), acidosis (1), pneumonitis (1), abdominal pain (1), colitis (1), AST elevation (1), weight loss (1), and hypokalemia (1). Grade II possibly related toxicities >20% included hypertension (46%), peripheral sensory neuropathy (31%), hypophosphatemia (31%), hypokalemia (31%), fatigue (31%), ALT increase (23%), elevated bili (23%), and myalgia (23%). Patients treated at the MTD experienced grade 3/4 possibly-related toxicities that were mainly laboratory based which included: neutropenia (4), anemia (2), hypophosphatemia (2), hypophosphatemia (1), hyponatremia (1), AST elevation (1), lymphopenia (1), abdominal pain (1), and colitis (1). The best overall response (CR+PR) rate was 67%, CR rate was 33%, PR 33%, stable disease rate was 25%, 1 patient was inevaluable. The best overall response rate for patients treated at dose level 1 and 2 was 67% with a CR of 44%. Median number of cycles was 4 (1-14). 2 patients went to autoHCT and 2 patients went to alloHCT after protocol. Conclusion: Addition of CsA to BV is safe and feasible at the MTD. The MTD was determined to be 1.8 mg/kg BV every 21 days plus 5 mg/kg of CsA PO BID on D 1-5. The ORR of 67% and CR of 33 % is very encouraging in a primary BV refractory population. The study has opened the expansion phase. Table 1. Table 1. Disclosures Chen: Millennium Pharmaceuticals: Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau; Genentech Inc.: Consultancy; Affimed: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Herrera:Seattle Genetics: Research Funding; Merck, Inc.: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding; Gilead Sciences: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; KiTE Pharma: Consultancy, Research Funding; Immune Design: Research Funding. Siddiqi:Juno Therapeutics: Other: Steering committee. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

Phase 1 Trial of Sorafenib and Everolimus In Patients with Lymphoma or Multiple Myeloma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2802-2802 ◽  
Author(s):  
Shaji Kumar ◽  
Luis F Porrata ◽  
Stephen M. Ansell ◽  
Joseph P Colgan ◽  
Betsy LaPlant ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Level ◽  
Research Funding ◽  
Phase 1 ◽  
Hematologic Toxicity ◽  
Phase 2 ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 2802 Background: Redundancy of pro-survival signaling pathways promotes survival and drug resistance in lymphoid and plasma cell malignancies. In particular, the PI3K-Akt and the MEK-ERK pathways have been shown to play an important role in the proliferation and survival of these malignant cells induced by various cytokines in the tumor microenvironment. Sorafenib, a Raf kinase and VEGF receptor inhibitor, and everolimus, an mTOR inhibitor, have synergistic cytotoxicity in myeloma and lymphoma cells due to inhibition of multiple signaling pathways. Methods: We designed a Phase 1/2 clinical trial to identify the maximum tolerated doses of the two drugs used in combination and the efficacy of the combination. Patients (Pts) with relapsed myeloma or lymphoma were eligible for enrollment. Pts were required to have an absolute neutrophil count ≥1500 × 10(6)/L, a platelet count ≥75,000, and a serum creatinine 21.5 mg/dL. The study utilized the classic 3+3 design. Extensive pharmacokinetic studies were performed to better delineate potential drug interactions. Results: Twenty-six pts were accrued from August 2007 to February 2009. Four pts discontinued sorafenib during cycle 1 for various reasons (2 patient refusal, 1 unrelated medical condition and 1 physician discretion) and were excluded from MTD determination. An additional pt did not have measurable disease and was ineligible, leaving 19 pts with lymphoma (including 6 with Hodgkin lymphoma) and 2 with myeloma for phase I analysis. The pts had a median age of 56 years (range, 22, 69) and were heavily pretreated with a median of 4 prior therapies (range, 1–10). Eighteen (86%) had received a prior stem cell transplant. Four dose limiting toxicities were seen across all dose levels (Table). These included grade 3 vomiting (level 1), grade 4 thrombocytopenia (level 2 and 3, one each) and grade 2 hand and foot rash leading to treatment delay (level 3). Overall, 13 pts experienced a grade 3 or 4 hematologic toxicity. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia occurred in 19%, 43%, and 38% of pts, respectively. Four pts have experienced a grade 3 non-hematologic toxicity; no grade 4 non-hematologic toxicities were seen. Grade 3 non-hematologic toxicities included hypokalemia, weight loss, vomiting, hand-foot skin reaction, fatigue, and elevated alkaline phosphatase. Dose level 1 (sorafenib 200 mg and everolimus 5 mg daily) was best tolerated and was selected for phase 2 evaluation. The ORR was 33% (7/21;95% CI: 15–57%, Table) with 3 pts at dose level 0 (2 PR, 1 CR), one at level 2 (1 PR) and three at level 3 (2 PR, 1 CR) responding. The responders included 5 pts with Hodgkin's disease and one each with an NK cell and T-cell lymphoma. Pts have received a median of 6 cycles (range: 1–19) of treatment. 16 pts have discontinued treatment due to disease progression (13 pts), non-resolution of cytopenias (1 pt), physician discretion (1 pt), and death on study due to lymphoma (1 pt). Disease progression has been seen in 16 pts; 9 pts have died. Median follow-up for pts still alive is 18.7 months (range: 11.5–29.4). 6 pts died from disease progression, one each due to sepsis unlikely related to treatment, cholecystitis, and unknown causes. Sorafenib is metabolized by the cytochrome P450 CYP3A enzyme and RAD-001 mainly by the CYP3A4 system in the liver, hence there is a potential for interactions. The detailed PK analyses performed as part of this trial showed a decrease in the RAD001 levels following initiation of sorafenib on day 8 of cycle 1 (Figure). Conclusion: The combination of sorafenib and everolimus is safe at a recommended phase 2 dose of sorafenib 200 mg and everolimus 5 mg daily. There is no significant drug interaction seen. Activity has been observed, especially in the setting of Hodgkins Disease. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Witzig:Novartis and Celgene: Patents & Royalties, Research Funding, Served on advisory boards with Novartis and Celgene – both uncompensated with compensation to Mayo Clinic.

Final Results Of a Phase I Study Of The Anti-CD79b Antibody-Drug Conjugate DCDS4501A In Relapsed Or Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (NHL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4400-4400 ◽  
Author(s):  
Maria Corinna Palanca-Wessels ◽  
Gilles Andre Salles ◽  
Myron S. Czuczman ◽  
Sarit E. Assouline ◽  
Ian W. Flinn ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
B Cell ◽  
Research Funding ◽  
Phase I Study ◽  
Sensory Neuropathy ◽  
Peripheral Sensory Neuropathy ◽  
Antibody Drug Conjugate ◽  
Grade 3 ◽  
Peripheral Sensory ◽  
Antibody Drug

Abstract Background DCDS4501A (DCDS), an anti-CD79b monoclonal antibody (Ab), is conjugated to the anti-mitotic agent MMAE. We previously determined a recommended Phase II dose (RP2D) of 2.4 mg/kg every 21 days (q21d), and clinical activity in R/R B-cell NHL at doses ≥ 1.8 mg/kg (Palanca-Wessels et al. ASH 2012). Here we update results from patients (pts) treated at 1.8 mg/kg and from the 2.4 mg/kg expansion cohort. Methods We evaluated ongoing safety, tolerability, pharmacokinetics (PK) and activity of DCDS with or without rituximab (RTX) at 375 mg/m2 q21d in pts with R/R DLBCL and indolent (i)NHL. Results Sixty pts were treated with DCDS (6 at 1.8 mg/kg, 45 at 2.4 mg/kg) and DCDS+RTX (9, DCDS at 2.4 mg/kg). Median age 68 yrs (range 20-86); 82% ECOG PS<2; median 4 prior regimens (range 1-14); 97% had prior RTX; 28% had prior autologous stem cell transplant. The DCDS+RTX safety profile did not differ from DCDS monotherapy. Patients received a median of 7 cycles (range 1-20) of DCDS and 10 cycles (range 1-17) of DCDS + RTX; 18 patients continue to receive study treatment. Treatment-emergent adverse events (TEAEs) included neutropenia (50%), diarrhea (45%), nausea (40%), pyrexia (38%), peripheral neuropathy (25%), peripheral sensory neuropathy (20%), and hypokalemia (20%). Grade ≥ 3 AEs in ≥5% of pts included neutropenia (43%), anemia (13%), thrombocytopenia (7%), hyperglycemia (7%), fatigue (5%) and diarrhea (5%). Grade ≥ 3 infection was reported in 8 (13%) pts. Twenty-two (37%) pts reported a serious AE. TEAEs related to peripheral neuropathy (PN) were reported in 32 (53%) pts with median time to first onset of 63 days. 22/32 pts (69%) had worsening PN with median time to worsening of 49 days. Grade ≥ 3 peripheral neuropathy/peripheral sensory neuropathy/peripheral motor neuropathy was reported in 5 (8%) patients. PN was managed with dose delays and dose reductions resulting in complete reversal in 7 (22%) pts. Treatment discontinuations for AEs were reported in 25 (42%) pts including 17 for PN. Seven pts (12%) had ≥ 1 dose reduction including 3 for PN and 2 for neutropenia. Twenty-six patients (43%) had ≥ 1 dose delay including 14 for neutropenia and 6 for PN. Six deaths were reported within 60 days of last study treatment assessed as unrelated to DCDS. Exposure of Ab-conjugated (ac) MMAE, total Ab, and unconjugated MMAE increased with dose. Maximal concentrations of unconjugated MMAE were >100-fold lower than acMMAE with an average Cycle 1 value of 5-9 ng/mL at the 2.4 mg/kg ADC dose level. Moderate accumulation of acMMAE and total Ab on the q21d dosing schedule was observed with no accumulation of free MMAE. Overall objective responses were observed in 27/51 (53%) DCDS and 7/9 (78%) DCDS+RTX pts. Objective (OR) and complete responses (CR) by histology were as follows: The median PFS for DLBCL patients treated with DCDS or DCDS + RTX was 149 days. The median PFS for iNHL patients treated with DCDS or DCDS + RTX was 241 days. Conclusions DCDS and DCDS+RTX were generally well-tolerated. Neutropenia and PN were the principal toxicities. PN was reversible in some patients with dose delays and reductions. Encouraging anti-tumor activity was observed in heavily pretreated pts with R/R NHL. Updated results from this Phase I study will be presented. An ongoing randomized Phase II study of DCDS+RTX versus a CD22-directed ADC (DCDT2980S) with the same linker-cytotoxic agent in patients with R/R DLBCL and follicular lymphoma will further assess the efficacy of DCDS in the treatment of NHL. Additional studies of DCDS combined with immunochemotherapy are being planned. Disclosures: Palanca-Wessels: Genentech, inc.: Research Funding. Off Label Use: anti-CD79b Antibody-Drug Conjugate in r/r B-cell NHL. Salles:Genentech, inc.: Consultancy. Czuczman:Genentech, inc.: Consultancy, Honoraria. Flinn:Genentech, inc.: Research Funding. Sehn:Genentech, inc.: Consultancy, Honoraria, Research Funding. Tilly:Genentech, inc.: Honoraria. Advani:Genentech, inc.: Research Funding. Casasnovas:Genentech, inc.: Research Funding. Press:Genentech, inc.: Consultancy, Research Funding. Yalamanchili:Genentech, inc.: Employment. Kahn:Genentech, inc.: Employment. Lu:Genentech, inc.: Employment. Chai:Genentech, inc.: Employment. Chu:Genentech, inc.: Employment. Morschhauser:Genentech, inc.: Honoraria, Research Funding.

scholarly journals Phase I Trial of Systemic Administration of Vesicular Stomatitis Virus Genetically Engineered to Express NIS and Human Interferon, in Patients with Relapsed or Refractory Multiple Myeloma (MM), Acute Myeloid Leukemia (AML), and T-Cell Neoplasms (TCL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3268-3268
Author(s):  
Martha Q. Lacy ◽  
Kah-Whye Peng ◽  
Stephen J. Russell ◽  
Amylou C. Dueck ◽  
Mrinal M. Patnaik ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Tumor Burden ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Background: We previously reported successful treatment of myeloma with an oncolytic virus, MMV-NIS. Preexisting immunity against measles made use of that virus unsatisfactory. The Indiana strain of Vesicular Stomatitis Viruses (VSV) are being developed as anticancer drugs for the treatment of a variety of malignancies. To ensure tumor selective replication and spread, we designed the VSV to encode interferon beta. Expression of IFNβ also serves as a STING agonist to activate host immunity against the cancer. The sodium iodide symporter (NIS) is inserted as a reporter gene into the viral genome to enable noninvasive monitoring of viral spread using PET/CT imaging. We report a Phase I clinical trial of intravenous administration of VSV-IFNβ-NIS for relapsed hematological malignancies including MM, AML, and TCL. Methods: Arm A consisted of patients with low tumor burden. Arm B included patients with high tumor burden. Both arms consisted of a classical 3+3 phase I trial, starting at 5x10^9 TCID50 (dose level 1) through 5x10^11 TCID50 (dose level 4), given as a single IV dose. In order to obviate potential toxicity from high interferon levels, Arm B received ruxolitinib 15 mg twice daily for 10 days beginning on day -1. The primary objective was determining the maximum tolerated dose (MTD) of VSV-IFNβ-NIS alone and in combination with ruxolitinib; secondary objectives include estimating the safety profile and preliminary efficacy. Correlative objectives include monitoring the pharmacodynamics of viral replication through SPECT/CT imaging with NIS gene, viremia, virus shedding, changes in the immune profile of peripheral blood leukocytes, and immunohistochemistry for immune cell infiltrates in tumors. Adverse events (AEs) are reported herein based on CTCAE v4 with the exception of cytokine release syndrome (CRS) which is based on Lee (Blood 2014; 124(2):188-195) criteria. Results: To date, 10 patients have received IV VSV-IFNβ-NIS; 8 in Arm A and 2 in Arm B. In Arm A, 3 patients were treated at dose level 1, 3 at dose level 2 and 2 at dose level 3. At dose level 1, there were three grade 3 hematologic AEs (neutropenia [1], lymphopenia [2]), and no grade 3+ non-hematologic AEs. At dose level 2, there were two grade 3 hematologic AEs (anemia [1], lymphopenia [1]), and two grade 3 non-hematologic AEs (nausea [1], dehydration [1]). A grade 2 CRS by Lee criteria was also observed. At dose level 3, 2 patients have been enrolled and data are maturing for DLT evaluation. In Arm B (VSV + rux), 2 patients have been enrolled and data are maturing for dose limiting toxicity (DLT) evaluation. Other grade 1 and 2 toxicities have included fever, hypertension, headache, electrolyte abnormalities, nausea, vomiting, transient elevation of liver function tests and creatinine. All grade 1 and 2 toxicities resolved within 72 hours. Among the 6 patients evaluable for response, there was one partial remission (TCL patient treated at dose level 2), and 5 with progressive disease. Multiple cytokines increased at 4h post infusion of virus, but most returned to baseline levels by 24h.Viremia was detectable in all patients at the end of infusion, and to varying levels at 30 mins, 1, 2, 4, 24, 48h or 72 hours post virus infusion. No persistent viremia was observed. No infectious virus was recovered in buccal swabs or urine and neutralizing anti-VSV antibodies were present by day 29. Extensive immune phenotyping and ELIspot assays for shared antigens are ongoing. Conclusion: In the lowest dose levels tested to date, VSV-IFNβ-NIS has not led to any observed dose limiting toxicity. Dose escalation is ongoing and updated results will be reported. Disclosures Lacy: Celgene: Research Funding. Peng:Vyriad: Equity Ownership. Russell:Vyriad: Equity Ownership. Dueck:Bayer: Employment; Phytogine: Employment; Pfizer: Honoraria. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:spectrum: Consultancy, Honoraria; Physicians Education Resource: Consultancy; Ionis: Honoraria; janssen: Consultancy; Medscape: Consultancy; celgene: Consultancy; Apellis: Consultancy; Prothena: Honoraria; Amgen: Consultancy; annexon: Consultancy; Abbvie: Consultancy; Research to Practice: Consultancy; Teva: Consultancy; Alnylam: Honoraria. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Al-Kali:Novartis: Research Funding. Naik:Vyriad: Equity Ownership. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

A phase I trial of plinabulin in combination with nivolumab and ipilimumab in patients with relapsed small cell lung cancer (SCLC): Big Ten Cancer Research Consortium (BTCRC-LUN17-127) study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8570-8570
Author(s):  
Jyoti Malhotra ◽  
Nasser H. Hanna ◽  
Alberto Chiappori ◽  
Lawrence Eric Feldman ◽  
Naomi Fujioka ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase I Study ◽  
Infusion Reaction ◽  
Phase 2 ◽  
Vascular Disrupting Agent ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

8570 Background: Plinabulin (BPI-2358) is a vascular disrupting agent with immune-enhancing function by inducing dendritic cell maturation and decreasing regulatory T cells. Preclinical studies report that plinabulin potentiates the cytotoxicity of dual checkpoint inhibition (CPI) with nivolumab and ipilimumab. Plinabulin may also reduce immune-related AEs from CPI through its phosphodiesterase-4 (PDE4) inhibitory activity which is associated with anti-inflammatory effects. We report initial results from a Phase I study assessing plinabulin in combination with nivolumab and ipilimumab. Methods: In this dose-escalation phase I study, patients with extensive-stage SCLC who had progressed on or after prior platinum-based chemotherapy (±CPI) were enrolled using a 3+3 design. The primary objective was to determine dose-limiting toxicities (DLT’s) and recommended Phase 2 dose (RP2D). Patients received nivolumab (1 mg/kg), ipilimumab (3 mg/kg) and plinabulin (as per dose escalation schema) IV on day 1 of each 21 day cycles. After completion of 4 cycles, patients continued therapy with nivolumab (240 mg) and plinabulin every 2 weeks till progression or intolerable toxicity. Patients were evaluable for DLT if they received at least 2 cycles of therapy; DLT period was defined as the first 6 weeks from C1D1. Secondary endpoints were ORR, PFS and frequency of irAEs. Correlative analysis included inflammatory biomarkers: hsCRP, ESR, SAA and haptoglobin. Results: Between 9/2018 and 11/2020, 17 patients were enrolled (1 patient withdrew consent before treatment, 16 were evaluable for safety). Median age was 59 years (range 43 to 78); 9 patients were male and 10 had received prior CPI. Eight patients were treated at dose-level 1 of plinabulin (20 mg/m2) and 8 patients at 30 mg/m2 of plinabulin (level 2); dose-level 2 was determined to be RP2D. There were 2 DLTs; 1 at dose-level 1 (grade 3 altered mental status lasting < 24 hours) and 1 at dose-level 2 (grade 3 infusion reaction). The most common treatment-related AEs (all grades) were nausea (10; 63%), infusion reaction (8; 50%), vomiting (7; 44%), diarrhea (7; 44%) and fatigue (6, 32%). Seven patients (44%) had at least one grade 3 or higher treatment-related AE; there were no treatment-related deaths. Two patients (13%) had grade 3 or higher irAE requiring steroids (1 colitis, 1 transaminitis); both at dose-level 1. At data cutoff (12/30/20), there were 3 PRs in CPI naïve patients (3/6; 50%) and 2 PRs in evaluable CPI-resistant patients (2/7; 29%). In the two CPI-resistant patients with confirmed response, the tumor reduction was 68% and 52%. Conclusions: Plinabulin in combination with nivolumab and ipilimumab was safe and well tolerated. A phase 2 study in CPI-experienced patients with relapsed SCLC is planned to confirm the preliminary signals of clinical activity and reduced immune toxicity. Clinical trial information: NCT03575793.

scholarly journals Results of an Ongoing Phase 2 Study of Brentuximab Vedotin with Rchp As Frontline Therapy in Patients with High-Intermediate/High-Risk Diffuse Large B Cell Lymphoma (DLBCL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 104-104 ◽  
Author(s):  
Lihua E. Budde ◽  
Ahmad Halwani ◽  
Christopher A. Yasenchak ◽  
Charles Michael Farber ◽  
John M Burke ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
High Risk ◽  
Research Funding ◽  
Sensory Neuropathy ◽  
Brentuximab Vedotin ◽  
Peripheral Sensory Neuropathy ◽  
Genetics Research ◽  
Equity Ownership ◽  
Grade 3 ◽  
Peripheral Sensory

Abstract Introduction DLBCL is the most common lymphoid neoplasm in adults (Swerdlow 2016). While durable CRs are achieved in approximately 70% of patients (pts) with frontline RCHOP therapy (Pfreundschuh 2008), pts with high-risk features often experience disease resistance or relapse. In Part 1 of an ongoing study, pts with high-intermediate or high risk DLBCL by international prognostic index (IPI) scores, regardless of CD30 expression by IHC, were treated with 1.2 or 1.8 mg/kg brentuximab vedotin (BV) combined with RCHOP. After 3 of the first 10 pts treated at 1.8 mg/kg BV+RCHOP developed Grade 3 peripheral neuropathy (per Standardized MedDRA Query [SMQ]), all pts enrolled subsequently received treatment with 1.2 mg/kg BV+RCHOP. Following completion of enrollment in Part 1, the protocol was amended to enroll a non-randomized portion of the study (Part 2) evaluating the safety and efficacy of 1.8 mg/kg BV+RCHP (Yasenchak 2015), followed by an open-label, randomized portion comparing BV+RCHP to RCHOP (Part 3). Initial results from Part 2 and updated results from Part 1 are reported here. Methods For Part 2 of the study, pts with CD30-expressing high-intermediate and high-risk DLBCL were treated with up to 6 cycles of 1.8 mg/kg BV+RCHP (NCT01925612). Key inclusion criteria were CD30 expression by IHC performed by a local pathology lab and standard IPI scores of 3-5 or age-adjusted IPI (aaIPI) scores of 2-3 (high-intermediate/high risk). CD30 expression was confirmed by a central pathology lab, although CD30 expression by local pathology lab was required for eligibility. Disease response was evaluated with PET/CT per Cheson 2007. Results At the time of analysis for this ongoing study, 11 pts in Part 2 were treated with BV+RCHP (7 male, 4 female; 22-78 yrs). Of these pts, 9 had high-intermediate risk (IPI 3, aaIPI 2) and 2 had high risk disease (IPI 4-5, aaIPI 3), 6 had Stage IV disease, and 6 had an ECOG score of 2. At the end of treatment, the overall response rate was 91% (9 CR, 1 PR); 1 pt had PD after Cycle 4. The most frequent (>20%) treatment-emergent adverse events (AEs) were alopecia and nausea (73% each); fatigue (64%); constipation and peripheral sensory neuropathy (55% each); neutropenia and throat irritation (36% each); and chills, diarrhea, headache, and stomatitis (27% each). Grade 3 or 4 AEs occurred in 8 pts and 5 pts had serious AEs, which included febrile neutropenia, bacteremia, nausea, pneumocystis jiroveci pneumonia, pulmonary embolism, and vomiting. Peripheral sensory neuropathy occurred in 6 pts and all were Grade 1 or 2 events; no peripheral motor neuropathy AEs were reported. No AEs were fatal or led to discontinuation. One pt discontinued treatment after Cycle 4 due to disease progression. For the first 51 pts in Part 1, the progression-free survival (PFS) at 18 months for pts with CD30 expression (25 pts) or without detectable CD30 expression (24 pts) by IHC was 79% (95% CI: 57%, 91%) versus 58% (95% CI: 36%, 75%), respectively. Overall survival for pts was 92% (95% CI: 71%, 98%) versus 71% (95% CI: 48%, 85%), respectively. Ten pts had pre-existing peripheral neuropathy (per SMQ) at study entry. Treatment-emergent peripheral neuropathy (per SMQ) was observed in 75% of pts (38/51) who received BV+RCHOP; 55% of these pts (21/38) had resolution of all or some peripheral neuropathy events. Conclusions 1.8 mg/kg BV+RCHP is active as frontline treatment in CD30-expressing, high-intermediate/high risk DLBCL. When combined with RCHP, 1.8 mg/kg BV appears to be well-tolerated. The PFS and OS for pts with CD30-expression who received BV+RCHOP appear promising. The study is currently ongoing in pts with CD30-expressing high-intermediate/high risk DLBCL to assess the safety and activity of 1.8 mg/kg BV+RCHP versus standard RCHOP. Disclosures Halwani: Bristol Myers-Squibb: Research Funding; Kyowa Hakko Kirin: Research Funding; Takeda: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Other: Travel Expenses, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; Miragen: Research Funding; Pharmacyclics: Consultancy; Amgen: Research Funding. Yasenchak:Seattle Genetics: Research Funding. Farber:Seattle Genetics: Research Funding. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Fayad:Seattle Genetics: Consultancy, Research Funding. Holkova:Seattle Genetics: Research Funding. Knapp:Insys Therapeutics, Inc.: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Kolibaba:Gilead: Consultancy, Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; janssen: Research Funding; GSK: Research Funding; Genentech: Research Funding; Acerta: Research Funding. Patel-Donnelly:Seattle Genetics: Research Funding. Yimer:Ariad Pharmaceuticals: Consultancy; Biotheranostics: Consultancy; Bluebird Bio: Equity Ownership; Kite Pharma: Equity Ownership; Clovis Oncology: Equity Ownership; Juno Therpeutics: Equity Ownership; Seattle Genetics: Research Funding. Smith:Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Research Funding. Levy:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau; Seattle Genetics: Research Funding; Actinium Pharmaceuticals, Inc.: Research Funding. Seetharam:Seattle Genetics: Research Funding. Belada:Seattle Genetics: Research Funding. Brooks:Seattle Genetics: Research Funding. Kingsley:Gilead: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Wagner-Johnston:Seattle Genetics: Research Funding. Ruffner:Forma Therapeutics: Consultancy; Sydnax: Consultancy; Seattle Genetics: Employment, Equity Ownership; Array Biopharma: Employment; Medivation: Employment. Bartlett:Gilead: Consultancy.

Efficacy and Safety of Ixabepilone (BMS-247550) in a Phase II Study of Patients With Advanced Breast Cancer Resistant to an Anthracycline, a Taxane, and Capecitabine

2007 ◽  
Vol 25 (23) ◽  
pp. 3407-3414 ◽  
Author(s):  
Edith A. Perez ◽  
Guillermo Lerzo ◽  
Xavier Pivot ◽  
Eva Thomas ◽  
Linda Vahdat ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Sensory Neuropathy ◽  
Efficacy And Safety ◽  
Peripheral Sensory Neuropathy ◽  
Metastatic Setting ◽  
Grade 3 ◽  
Peripheral Sensory

PurposeTo evaluate the efficacy and safety of ixabepilone in patients with metastatic breast cancer (MBC) resistant to anthracycline, taxane, and capecitabine, in this multicenter, phase II study.Patients and MethodsPatients with measurable disease who had tumor progression while receiving prior anthracycline, taxane, and capecitabine were enrolled. Ixabepilone 40 mg/m2monotherapy was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle. The primary end point was objective response rate (ORR), assessed by an independent radiology facility (IRF).ResultsA total of 126 patients were treated and 113 were assessable for response. Patients were heavily pretreated: 88% had received at least two lines of prior chemotherapy in the metastatic setting. IRF-assessed ORR was 11.5% (95% CI, 6.3% to 18.9%) for response-assessable patients. Investigator-assessed ORR for all treated patients was 18.3% (95% CI, 11.9% to 26.1%). Fifty percent of patients achieved stable disease (SD); 14.3% achieved SD ≥ 6 months. Median duration of response and progression-free survival were 5.7 and 3.1 months, respectively. Median overall survival was 8.6 months. Patients received a median of 4.0 treatment cycles (range, one to 16 cycles), and 25% of patients received ≥ eight cycles. Grade 3/4 treatment-related events included peripheral sensory neuropathy (14%), fatigue/asthenia (13%), myalgia (8%), and stomatitis/mucositis (6%). Resolution of grade 3/4 peripheral sensory neuropathy occurred after a median period of 5.4 weeks.ConclusionIxabepilone demonstrated clear activity and a manageable safety profile in patients with MBC resistant to anthracycline, taxane, and capecitabine. Responses were durable and notable in patients who had not previously responded to multiple prior therapies.

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