A Multicenter Randomized Phase II Trial of Mapatumumab, a TRAIL-R1 Agonist Monoclonal Antibody, In Combination with Bortezomib In Patients with Relapsed/Refractory Multiple Myeloma (MM)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5031-5031 ◽  
Author(s):  
Andrew Belch ◽  
Atul Sharma ◽  
Andrew Spencer ◽  
Stefano Tarantolo ◽  
Nizar J Bahlis ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Human Monoclonal Antibody ◽  
Progression Free Survival ◽  
Complete Response ◽  
P Value ◽  
Employment Equity ◽  
Duration Of Response ◽  
Equity Ownership

Abstract Abstract 5031 Mapatumumab, a fully human monoclonal antibody, targets and activates the TRAIL-R1 receptor. We conducted this randomized, controlled phase II trial to evaluate the efficacy and safety of mapatumumab in combination with bortezomib in subjects with relapsed/refractory MM. Response was evaluated using the Bladé criteria. Patients were required to have a measurable serum and/or urine M-protein and have failed 1 or 2 prior therapies for MM. Patients were excluded if they had received prior bortezomib. Patients were randomly assigned to Arm A, 1.3 mg/m2 bortezomib (days 1, 4, 8, 11) every 21 days; Arm B10, bortezomib + 10 mg/kg mapatumumab (day 1) every 21 days; or Arm B20, bortezomib + 20 mg/kg mapatumumab (day 1) every 21 days. Cycles were repeated every 21 days for a maximum of 17 cycles (1 year), progressive disease or unacceptable toxicity. Subjects with complete response (CR) were treated for an additional 2 cycles after documentation of CR (not to exceed 17) and then followed. A total of 104 subjects from 4 countries were randomly assigned to the treatment arms. The addition of mapatumumab to bortezomib did not increase the response rate, progression-free survival (PFS) or duration of response compared to bortezomib alone. Adverse events were generally balanced across treatment groups; there was no evidence that mapatumumab exacerbated toxicities associated with bortezomib. As expected, the most common toxicities were hematological and peripheral neuropathies. The results do not support further evaluation of mapatumumab in combination with bortezomib in patients with advanced MM. Additional trials of mapatumumab in other indications are on-going. Arm A (n= 35) Arm B10 (n=33) Arm B20 (n=36) CR 0 0 2 PR 18 10 17 CR + PR n (%) 18 (51.4) 10 (30.3) p=0.08a 19 (52.8) p=0.91b Median PFS mo (95% CI) 8.7 (7.6, 10.0) 4.7 (2.5, 7.4) p=0.29a 5.7 (5.2, 8.9) p=0.21b Median Duration of Response mo (range) 8.5 (6.9, 14.2) 9.3 (3.9, 16.1) p=0.92a 7.6 (4.3, 8.8) p=0.41b a P value for comparison of Arm A with Arm B10 b P value for comparison of Arm A with Arm B20 Disclosures: Gallant: Human Genome Sciences, Inc.: Employment, Equity Ownership. Kumm:Human Genome Sciences, Inc.: Employment, Equity Ownership. Klein:Human Genome Sciences, Inc.: Employment, Equity Ownership.

A randomized phase II trial of mapatumumab, a TRAIL-R1 agonist monoclonal antibody, in combination with carboplatin and paclitaxel in patients with advanced NSCLC.

2010 ◽  
Vol 28 (18_suppl) ◽  
pp. LBA7501-LBA7501 ◽  
Author(s):  
J. Von Pawel ◽  
J. H. Harvey ◽  
D. R. Spigel ◽  
M. Dediu ◽  
M. Reck ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Disease Progression ◽  
Phase Ii ◽  
Advanced Nsclc ◽  
Phase Ii Trial ◽  
Death Receptor ◽  
Progression Free Survival ◽  
Complete Response ◽  
First Line Therapy ◽  
Group Assignment

LBA7501 Background: Mapatumumab, a fully human agonist monoclonal antibody, targets and activates the death receptor TRAIL-R1. We conducted this randomized, controlled phase II trial to evaluate mapatumumab in combination with carboplatin and paclitaxel as first-line therapy in advanced non-small call lung cancer (NSCLC). Methods: Patients were required to have histologically or cytologically confirmed Stage IIIB or IV advanced primary NSCLC with measurable disease by RECIST. Patients were randomly assigned to Arm A, paclitaxel 200 mg/m2 + carboplatin AUC 6.0 (PC); Arm B, PC + mapatumumab 10 mg/kg; or Arm C, PC + mapatumumab 30 mg/kg. Cycles were repeated every 21 days; patients completed up to 6 cycles in the absence of evidence of disease progression or unacceptable toxicity. Patients in Arms B and C could receive additional cycles of mapatumumab in the absence of disease progression. The co-primary endpoints were response rate (RR; complete response + partial response) and progression-free survival (PFS). Images were read by independent radiologists blinded to treatment group assignment, as well as locally. Results: 111 patients were enrolled at 22 sites in 4 countries. Addition of mapatumumab to PC did not improve RR or PFS. RR and PFS, based on the independent read, and overall survival results are summarized below. The results based on local reading also showed no benefit from the addition of mapatumumab to PC. Adverse events were generally balanced across treatment groups; there was no evidence that mapatumumab exacerbated toxicities associated with PC. Conclusions: The results do not support further evaluation of mapatumumab in combination with PC in patients with advanced NSCLC. Additional trials of mapatumumab in other indications are ongoing. [Table: see text] [Table: see text]

Phase II consolidation trial with anti-Lewis-Y monoclonal antibody (hu3S193) in platinum-sensitive ovarian cancer after a second remission

2021 ◽  
pp. ijgc-2020-002239
Author(s):  
Oren Smaletz ◽  
Gustavo Ismael ◽  
Maria Del Pilar Estevez-Diz ◽  
Ivana L O Nascimento ◽  
Ana Luiza Gomes de Morais ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Monoclonal Antibody ◽  
Epithelial Ovarian Cancer ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Complete Response ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Platinum Based Chemotherapy ◽  
Lewis Y

ObjectiveTo investigate the efficacy and safety of hu3S193, a humanized anti-Lewis-Y monoclonal antibody, as a consolidation strategy in patients with platinum-sensitive recurrent epithelial ovarian cancer who achieved a second complete response after salvage platinum-doublet chemotherapy.MethodsThis single-arm phase II study accrued patients with recurrent epithelial ovarian cancer with Lewis-Y expression by immunohistochemistry who had achieved a second complete response after five to eight cycles of platinum-based chemotherapy. Patients received intravenous infusions of hu3S193, 30 mg/m2 every 2 weeks starting no more than 8 weeks after the last dose of chemotherapy and continuing for 12 doses, until disease progression, or unacceptable toxicity. The primary endpoint was progression-free survival of the second remission. Secondary objectives were safety and pharmacokinetics.ResultsTwenty-nine patients were enrolled. Most had a papillary/serous histology tumor (94%), stage III disease at diagnosis (75%), and five (17%) underwent secondary cytoreduction before salvage chemotherapy. Two patients were not eligible for efficacy but were considered for toxicity analysis. Eighteen patients (62%) completed the full consolidation treatment while nine patients progressed on treatment. At the time of analysis, 23 patients (85%) of the eligible population had progressed and seven of these patients (26%) had died. Median progression-free survival of the second remission was 12.1 months (95% CI: 10.6–13.9), with a 1-year progression-free survival of the second remission rate of 50.1%. The trial was terminated early since it was unlikely that the primary objective would be achieved. The most commonly reported treatment-related adverse events were nausea (55%) and vomiting (51%).ConclusionsHu3S193 did not show sufficient clinical activity as consolidation therapy in patients with recurrent epithelial ovarian cancer who achieved a second complete response after platinum-based chemotherapy.Trial registrationNCT01137071.

Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers.

1998 ◽  
Vol 16 (8) ◽  
pp. 2739-2744 ◽  
Author(s):  
Y Bécouarn ◽  
M Ychou ◽  
M Ducreux ◽  
C Borel ◽  
F Bertheault-Cvitkovic ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Sensory Neuropathy ◽  
Progression Free Survival ◽  
Free Survival ◽  
Duration Of Response ◽  
Grade 3 ◽  
Colorectal Cancer Patients ◽  
Peripheral Sensory

PURPOSE To evaluate the objective tumor response rate and safety profile of oxaliplatin when administered to patients with previously untreated metastatic colorectal adenocarcinoma. PATIENTS AND METHODS A total of 39 patients were entered onto this phase II trial. One patient was excluded for having had a second cancer, so the study was based on 38 patients. Patients were treated with oxaliplatin 130 mg/m2 as a 2-hour infusion on day 1, every 21 days. Patients were assessed for response every three courses. All clinical and radiologic data were reviewed by an external panel of experts, with their assessment being considered definitive. RESULTS Nine partial responses (PRs) were observed (response rate, 24.3%; 95% confidence interval, 11.8% to 41.2%). The median duration of response was 216+ days. Fifteen patients (40.5%) had stable disease and 13 (35.2%) had progressive disease. The median progression-free survival time for all patients was 126+ days (range, 21 to 447+). The main toxicity was peripheral sensory neuropathy. Grade 3 neurotoxicity (National Cancer Institute common toxicity criteria [NCI-CTC]) was reported in 13%. Hematologic and gastrointestinal toxicities were mild. The incidence of grade 3 neutropenia was 5.2%, while that of grade 3 or 4 thrombopenia was 7.9%. Vomiting (grade 3 or 4) occurred in 7.9% of patients and grade 3 diarrhea in 2.6%. CONCLUSION This phase II study provides clear evidence of the safety and efficacy of oxaliplatin monotherapy at this dose and schedule in patients with previously untreated metastatic colorectal carcinoma.

Oligopelvis-GETUG P07: A multicenter phase II trial of combined salvage radiotherapy and hormone therapy in oligorecurrent pelvic node relapses of prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 93-93 ◽  
Author(s):  
Stephane Supiot ◽  
David Pasquier ◽  
Xavier Buthaud ◽  
Nicolas Magné ◽  
Veronique Beckendorf ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Hormone Therapy ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Progression Free Survival ◽  
Complete Response ◽  
Salvage Radiotherapy ◽  
Free Survival ◽  
Pelvic Node ◽  
Lh Rh

93 Background: Oligorecurrent pelvic nodal relapse of prostatic cancer is a challenge for regional salvage treatments. We conducted OLIGOPELVIS – GETUG P07, a phase II trial of combined salvage radiotherapy and hormone therapy in oligorecurrent pelvic node relapses of prostate cancer (NCT02274779). Methods: OLIGOPELVIS–GETUG P07 was a prospective multi-center phase II trial investigating high-dose salvage pelvic irradiation with an additional dose to the fluorocholine-based positron-emission-tomography (FCH- PET)-positive pelvic lymph nodes (PLN), combined with six-month androgen blockade (LH-RH agonist or antagonist injections). The prescribed dose was 54 Gy in 1.8 Gy fractions with up to 66 Gy in 2.2 Gy fractions to the pathological PLN. Toxicity (CTCAE v4) and complete response rates (PSA < 0.20 ng/ml) were analyzed. The main objective was to assess biochemical-clinical failure defined by a cluster of events including PSA progression (≥25 % and ≥ 2 ng/ml above the nadir) or clinical evidence of local or metastatic progression or post- treatment initiation of hormonal therapy or prostate cancer-related death. We hypothesized that salvage treatment would achieve a 2-year relapse-free survival of 70 %. Results: Seventy-four patients were recruited in fifteen French radiation oncology departments between August 2014 and July 2016. Seven were excluded before treatment because of violation of the inclusion criteria. The intention-to-treat analysis therefore included sixty-seven patients. Half of them had received prior prostatic/prostate bed irradiation. Median age was 67.7. Grade 2+ two-year urinary and intestinal toxicity were 10% and 2% respectively. At 2 and 3 years, 73.1 and 45.9% of patients achieved a persisting complete response respectively. After a median follow-up of 34 months, the 2-year progression-free survival rate was 77.6%. Median progression-free survival was 40.1 months. Conclusions: Combined pelvic salvage radiotherapy and hormone therapy allowed for prolonged tumor control in oligorecurrent pelvic node relapses of prostate cancer with limited toxicity. Clinical trial information: NCT02274779.

scholarly journals Minimal Residual Disease Status Predicts Progression-Free Survival in Newly Diagnosed Multiple Myeloma (NDMM) Patients Treated with Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone (KRd)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2127-2127 ◽  
Author(s):  
Jagoda Jasielec ◽  
Dominik Dytfeld ◽  
Kent A. Griffith ◽  
Kathryn McDonnell ◽  
Daniel Lebovic ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Free Survival ◽  
Kaplan Meier ◽  
Equity Ownership ◽  
Minimal Residual

Abstract Background: NDMM patients (pts) treated with KRd in a phase 1/2 trial (NCT01029054) demonstrated high rates of complete response (CR, 64%) and stringent complete response (sCR, 55%) that correlated with excellent estimated 3-year progression-free survival (PFS; 79%) and overall survival (OS; 96%) (Jakubowiak et al, Blood, 2012; Jasielec et al, Blood 2013; 122(21):3220). Furthermore, there was a trend towards superior outcomes in patients with multiparameter flow cytometry (MFC) MRD-negative disease with an estimated 3 year PFS of 84% and OS of 100%, suggesting the importance of MRD analysis in predicting relapse. In this post hoc, retrospective analysis, we present an updated evaluation of PFS based on minimal residual disease (MRD) status. Methods: Pts received 28-day cycles of carfilzomib (CFZ) 20–36 mg/m2 intravenously (days [d]1, 2, 8, 9, 15, 16), lenalidomide (LEN) 25 mg orally (PO; d1–21), and dexamethasone 40/20 mg PO weekly (cycles 1–4/5–8). For cycles 8–24, KRd was given with a modified CFZ schedule (d1, 2, 15, 16), and single-agent LEN was administered after cycle 24. Pts had the option to receive stem cell transplantation after cycle 4. MRD assessment at the time of complete response (CR) was performed using 10-color MFC and next-generation sequencing (NGS) analysis. Fresh bone marrow aspirate (BMA) was used for MFC analysis as previously reported, while archived BMA slides were used for NGS analysis. The LymphoSIGHT™ NGS method employed universal primer sets to assess clonal rearrangements at the immunoglobulin loci (IGH-VDJ, IGH-DJ and IGK) in diagnostic BMA slides. Myeloma clonotypes were identified in the diagnostic BMA sample of each patient based on high-frequency within the B-cell repertoire. The level of the myeloma clonotype was then quantified in BMA slides obtained at the time of CR. Results: Twenty-two pts with CR/sCR were evaluated for MRD by both MFC and NGS methods with a median follow-up of 40 months. Limited input DNA was obtained from BMA slides (range 2,189 to 1,870,960 cell equivalents). Concordance analysis in 21 patients with both MFC and NGS MRD data revealed 11 patients that were MRD-negative by both MFC and NGS, while 2 patients were concordantly MRD-positive. NGS demonstrated greater sensitivity compared to MFC, as 8 patients were MRD-positive by NGS but MRD-negative by MFC. Three of these 8 patients relapsed. We evaluated the correlation between MRD status by NGS and PFS. Six MRD samples had less than 40,000 input cell equivalents and were removed from the progression-free survival analysis due to insufficient sample amount. MRD negativity by NGS in KRd patients at the time of CR was associated with longer progression-free survival (median not reached vs 46 months, p = 0.055) (Figure 1). Conclusions: Our results suggest that achievement of MRD-negative disease by NGS in CR patients is associated with superior PFS. The NGS method appears more sensitive than MFC at detecting residual disease. Finally, MRD assessment by NGS in BMA slides is feasible although may not be the optimal method due to limited input DNA amount. MRD assessment by NGS will be performed on the remainder of the KRd cohort and results will be presented. Figure 1. Kaplan-Meier analysis of progression-free survival for 6 MRD negative (<10-6) and 10 MRD positive (>10-6) patients. Figure 1. Kaplan-Meier analysis of progression-free survival for 6 MRD negative (<10-6) and 10 MRD positive (>10-6) patients. Disclosures Faham: Sequenta, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Lee:Sequenta, Inc.: Employment, Equity Ownership. Jakubowiak:Bristol Myers-Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDx: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Phase I Trial of TGR-1202, a Next Generation Once-Daily PI3Kδ Inhibitor, in Combination with Brentuximab Vedotin, in Patients with Relapsed/Refractory Hodgkins Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4146-4146 ◽  
Author(s):  
Radhakrishnan Ramchandren ◽  
Carolyn M. Mulroney ◽  
Manish R. Patel ◽  
Peter Sportelli ◽  
Hari P. Miskin ◽  
...  
Keyword(s):  
Research Funding ◽  
Complete Response ◽  
Brentuximab Vedotin ◽  
Hodgkin's Lymphoma ◽  
Tolerability Profile ◽  
Employment Equity ◽  
Once Daily ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Ecog Ps

Abstract Introduction: TGR-1202 is a once daily, oral PI3Kδ inhibitor that has demonstrated activity in patients (pts) with relapsed and refractory hematologic malignancies, with a favorable safety and tolerability profile compared to other PI3Kδ inhibitors (Burris, ASCO 2016). Brentuximab vedotin (BV) is a CD30 specific antibody-drug conjugate, which is FDA approved for the treatment of Hodgkin's Lymphoma (HL) and Systemic Anaplastic Large-cell Lymphoma (sALCL). BV has demonstrated impressive response rates in pts with rel/ref disease, however the duration of response is short in pts not achieving a complete response (median PFS of ~6 months for non-CR pts; Gopal et al, Blood 2015). Marked synergy has been demonstrated pre-clinically with TGR + BV, with the combination demonstrating a 3-fold increase in cell death in-vitro and a 55% increase in tumor growth inhibition over either TGR or BV alone in an in-vivo xenograft model of HL (Locatelli et al, ASH 2014). As the combination of TGR + BV displays strong synergy pre-clinically and incorporates non-overlapping mechanisms of activity, a Phase 1 trial evaluating the combination of TGR + BV in pts with rel/ref HL was undertaken. Methods: Eligible pts have relapsed or refractory HL, have received prior ASCT or at least 2 prior regimens, and have an ECOG PS < 3. Prior BV exposure is allowed. Two dose cohorts for TGR are evaluated (400 and 600 mg) dosed once daily with a fixed dose of BV 1.8 mg/kg on day 1 of each cycle (Cycle = 21 days) until off study. Safety is the primary endpoint evaluated by CTCAE v. 4.0. Efficacy (ORR and duration of response) is a secondary endpoint with responses determined according to response criteria of the International Working Group (Cheson, JCO 2007). Results: Fourteen pts have been enrolled. Median age is 34 (range 21 - 81); 9 Male/5 Female; Median ECOG PS = 1; with a median of 3 prior therapies (range 2 - 6). Seven pts had prior ASCT. Six pts had previously received BV, and all 6 were refractory to prior BV therapy. All pts are evaluable for safety. The most common AEs regardless of causality were nausea (71%; 0% Gr. 3/4), diarrhea (57%; 7% Gr. 3/4), neutropenia (50%; 43% Gr. 3/4), and rash (43%; 7% Gr. 3/4), followed by cough, dyspnea, and vomiting (36% each, all grades). Peripheral neuropathy was reported in 4 pts (29%), and were all Grade 1/2. Eleven pts were evaluable for efficacy, with 3 discontinuing prior to first efficacy assessment (1 withdrew consent, and 2 due to AEs). The ORR was 64% (7/11), with 45% (5/11) achieving a complete response with a median TTR of 8 weeks. Notably, 50% (3/6) of BV refractory patients responded to TGR-1202 + BV combination therapy (2 CRs, 1 PR). Three responding patients proceeded to stem cell transplant. Of the remaining 4 patients achieving a response, 2 patients remain in CR, and 2 have progressed (at 13 and 16.5 mos respectively). Conclusions: The combination of TGR-1202 + brentuximab vedotin exhibits an acceptable tolerability profile and is clinically active. Responses were observed in patients with advanced Hodgkin's Lymphoma, including responses in 50% of patients previously refractory to brentuximab vedotin. Further studies evaluating this combination are warranted. Disclosures Sportelli: TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc: Employment, Equity Ownership. Chen:Genentech: Consultancy, Speakers Bureau; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau.

Phase II trial of sorafenib in esophageal (E) and gastroesophageal junction (GEJ) cancer: Response observed in adenocarcinoma.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 41-41 ◽  
Author(s):  
D. Ilson ◽  
Y. Y. Janjigian ◽  
M. A. Shah ◽  
L. H. Tang ◽  
D. P. Kelsen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stable Disease ◽  
Kinase Inhibitor ◽  
Phase Ii Trial ◽  
Gastroesophageal Junction ◽  
Single Agent ◽  
Progression Free Survival ◽  
Complete Response ◽  
Node Disease ◽  
Grade 3

41 Background: Sorafenib is a tyrosine kinase inhibitor targeting VEGFr, PDGFr, Raf and other pathways. Encouraging response and survival were observed in a phase II trial combining sorafenib with chemotherapy in GE cancer (J Clin Oncol 27:2947;2010). We are studying single agent sorafenib in a phase II trial with the primary endpoint to assess progression free survival (PFS). Secondary endpoints include response and therapy tolerance. Methods: Patients (pts) with measurable metastatic E and GEJ cancer with no more than 3 prior chemotherapy regimens were treated with sorafenib 400 mg BID. CT scans were performed monthly for the first 2 months, then every 2 months. Results: Sixteen of 35 pts have been accrued and 14 are currently evaluable. 13 male, 3 female, median KPS 80%, age 58, GEJ 7, E 9, squamous 2, adenocarcinoma (AC)14. An ongoing complete response (11+ months) was observed in a pt with biopsy proven metastatic neck lymphadenopathy (E primary AC, recurrence after prior chemoradiotherapy and surgery). A second pt (GEJ AC) had protracted stable disease in bulky celiac node disease (15+ months). Grade 3 toxicity was limited to skin rash (1 pt), hand foot reaction (1 pt), and fatigue (1 pt). Only 3 of 14 pts (21%) had early disease progression at 2 months or less. Median PFS 4 mos, 4 patients (29%) continue on therapy for more than 7 months. The majority of tumors tested positive for phospho-erk by immunohistochemistry (11/14, 79%). Conclusions: The observation of a durable complete response and protracted stable disease to sorafenib in E cancer is remarkable. Further accrual continues to define PFS. Supported by a grant from Bayer. [Table: see text]

Clinical trial in progress: Phase II trial of defactinib (VS-6063) combined with VS-6766 (CH5126766) in patients with metastatic uveal melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9588-TPS9588
Author(s):  
Rino S. Seedor ◽  
Marlana Orloff ◽  
J. Silvio Gutkind ◽  
Andrew E. Aplin ◽  
Mizue Terai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Uveal Melanoma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Human Cancer ◽  
Progression Free Survival ◽  
Complete Response ◽  
Total Sample ◽  
Oncogenic Signaling ◽  
Pharmacodynamic Profile

TPS9588 Background: Despite successful treatment of primary uveal melanomas (UM), up to 50% of patients subsequently develop systemic metastasis, with the liver involved in up to 90% of patients. Currently there is no US FDA-approved treatment for metastatic uveal melanoma (MUM). Activating mutations in genes encoding alpha subunits of the heterotrimeric G proteins, GNAQ and GNA11, are found in 80-90% of UM. Recent information suggests that GNAQ/GNA11-oncogenic signaling involves a non-canonical pathway conferring the activation of YAP1, distinct from the activation of PLCβ and PKC-MEK-ERK, which may explain the failure of MEK inhibitors in MUM patients. Focal Adhesion Kinase (FAK) is a tyrosine kinase that provides a direct link between Gαq and tyrosine phosphorylation networks controlling YAP and UM growth. Interestingly, UM represents the human cancer harboring the highest level of FAK overexpression. Recent kinome-wide CRISPR-Cas9 screens revealed that FAK and RAF/MEK co-targeting may provide a new network-based precision therapeutic strategy for MUM treatment. Methods: This is an investigator-initiated, prospective, single arm, single-institution, phase II trial evaluating the combination of a FAK inhibitor (defactinib, VS-6063) with a RAF/MEK inhibitor (VS-6766, CH5126766) for the treatment of patients with metastatic uveal melanoma [NCT04720417]. The primary endpoint of the study is disease control rate (DCR) of 50% including complete response (CR), partial response (PR), and stable disease (SD) as determined by RECIST criteria version 1.1. Secondary endpoints include progression free survival, overall survival, and causality of adverse events. Exploratory endpoints include analysis of the pharmacodynamic profile, mechanism of resistance to the combination, and investigation of circulating free DNA as a biomarker. The efficacy of this combination treatment will be assessed using the Simon’s two stage design. In stage I, a total number of 8 patients are accrued and if there are 2 or fewer overall responses among these 8 patients, further enrollment of patients may be stopped with the conclusion that DCR cannot be 50% or greater. Otherwise, an additional 10 patients will be accrued in stage II, resulting in a total sample size of 18 patients. Patients at 18 years or older with metastases from uveal melanoma will be eligible (any line of therapy). Defactinib (200 mg) will be administered orally twice a day in combination with VS-6766 (3.2 mg) administered orally twice a week for 3 weeks, in 28-day cycles. Dose modification will be considered based on toxicity. Treatment will be continued until maximum clinical benefit is obtained; disease progression or the development of intolerable side effects. Enrollment to stage 1 began in February 2021. Clinical trial information: NCT04720417.

The Bruton's Tyrosine Kinase Inhibitor PCI-32765 Is Highly Active As Single-Agent Therapy in Previously-Treated Mantle Cell Lymphoma (MCL): Preliminary Results of a Phase II Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 442-442 ◽  
Author(s):  
Luhua Wang ◽  
Peter Martin ◽  
Kristie A. Blum ◽  
Brad S. Kahl ◽  
Lauren S. Maeda ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Employment Equity ◽  
Mantle Cell ◽  
Previously Treated ◽  
Equity Ownership

Abstract Abstract 442 Introduction: Bruton's tyrosine kinase (Btk) is a central mediator of B-cell receptor signaling which is essential for normal B-cell development. PCI-32765 is an orally administered irreversible inhibitor of Btk that induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. In a phase I trial of PCI-32765 in relapsed B-cell malignancies, objective responses were observed in seven of nine patients with MCL. Reported here are preliminary results of an ongoing phase II study of single-agent PCI-32765 in previously treated MCL. Methods and Patients: Patients with relapsed or refractory MCL who were either bortezomib-naïve or bortezomib-exposed (prior treatment with at least 2 cycles of bortezomib) were eligible for study PCYC-1104. PCI-32765 was administered orally at 560mg daily (in continuous 28-day cycles) until disease progression. Bortezomib-naive and bortezomib-exposed cohorts were evaluated separately. Tumor response was evaluated every 2 cycles and classified by 2007 NHL IWG criteria. Results: A total of 48 patients (29 bortezomib-naive, 19 bortezomib-exposed) have been enrolled on study PCYC-1104 between February 16, 2011 and July 20, 2011. The median age is 67 years (62–72). The median number of prior treatment regimens is 2 (1–5). Five patients (13%) had received prior autologous or allogeneic stem cell transplantation. Seven patients (15%) had bulky disease. Thirty-nine patients who have initiated treatment and have reported adverse event (AE) information are the subject of this preliminary report. Twenty-four patients (12 bortezomib-naive, 12 bortezomib-exposed) have undergone at least 1 follow-up tumor assessment and are evaluable for efficacy. Treatment has been well tolerated. No patients have discontinued treatment due to AEs. Grade 1 or 2 diarrhea, fatigue, and nausea have been the most frequently reported AEs. Grade >3 AEs considered potentially related to PCI-32765 have occurred in 4/39 patients (11%). Serious AEs (SAEs) have occurred in 8/39 patients (21%); 2 SAEs (1 rash, 1 febrile neutropenia) were considered potentially related to PCI-32765. One death, in a patient who was enrolled but did not receive PCI-32765 due to rapid disease progression, has occurred on study. The objective response rate (ORR) by IWG criteria is 67% (16/24); ORR is 58% (7/12) in the bortezomib-naive cohort and 75% (9/12) in the bortezomib-exposed cohort. To date, 35/39 patients remain on PCI-32765; reasons for discontinuation include progressive disease (n=3) and investigator decision (n=1). Conclusions: Preliminary data from a phase II trial suggests that the potent Btk inhibitor PCI-32765 is well tolerated and induces a high rate of objective responses in patients with relapsed or refractory MCL. More mature safety and efficacy data will be updated in the presentation. Phase III trials of PCI-32765 in MCL are planned. Disclosures: Wang: Pharmacyclics: Research Funding. Off Label Use: PCI-32765 in mantle cell lymphoma in a phase 2 clinical trial. Martin:Pharmacyclics: Research Funding. Blum:Pharmacyclics: Research Funding. Kahl:Pharmacyclics: Research Funding. Maeda:Pharmacyclics: Research Funding. Advani:Pharmacyclics: Research Funding. Williams:Pharmacyclics: Research Funding. Rule:Pharmacyclics: Research Funding. Rodriguez:Pharmacyclics: Employment, Equity Ownership. Pang:Pharmacyclics: Consultancy. Hedrick:Pharmacyclics: Employment, Equity Ownership. Goy:Pharmacyclics: Research Funding.

PILLAR-1: Preliminary Results of a Phase II Study of mTOR Inhibitor Everolimus In Patients with Mantle Cell Lymphoma (MCL) Who Are Refractory or Intolerant to Bortezomib

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3963-3963 ◽  
Author(s):  
Owen A. O'Connor ◽  
Leslie Popplewell ◽  
Jane N. Winter ◽  
RuiRong Yuan ◽  
Anna Robeva ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Initial Diagnosis ◽  
Survival Duration ◽  
Employment Equity ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Stage 1

Abstract Abstract 3963 Introduction: MCL remains incurable with current therapeutic approaches. Bortezomib is approved for patients with relapsed MCL, though the duration of response is limited. As such, there is a critical need for novel therapeutic strategies and targeted agents. The mammalian target of rapamycin (mTOR) pathway is aberrantly activated in many hematologic malignancies. Studies of monotherapy everolimus, an oral inhibitor of mTOR, have shown substantial antitumor activity in relapsed aggressive non-Hodgkin's lymphoma and other types of relapsed or refractory lymphomas, including MCL. Methods: PILLAR-1 (PIvotaL Lymphoma triAls of RAD001-1) is an open-label, US-based, multicenter, single-arm, phase II study (clinicaltrials.gov: NCT00702052) of oral everolimus (RAD001) 10 mg/d in patients with pathologically confirmed MCL who are bortezomib refractory (defined as radiological progression ≤12 months after the last bortezomib-containing combination or monotherapy) or intolerant (defined as requiring discontinuation due to toxicity). Study treatment with everolimus continued until disease progression, unacceptable toxicity, death, or study discontinuation. Eligible patients have received ≥1 prior antineoplastic agent other than bortezomib either separately or in combination with bortezomib. The primary endpoint is objective response rate (ORR including complete response [CR] and partial response [PR]). Secondary endpoints include progression-free survival, overall survival, duration of response, and safety. A Simon two-stage design was used and was based on ORR among 34 treated patients in Stage 1. If ≥3 CR or PR occurred in Stage 1, an additional 23 patients would be treated in Stage 2; otherwise, the study would be stopped. Results presented here are based on a data cut-off of April 26, 2010. Results: A preliminary analysis of efficacy and safety included 26 patients (65% male) with the following baseline characteristics: median age 65 y (range, 50–83); 77% were >2 y post initial diagnosis; 72% had previously received ≥3 therapies; 89% had previously relapsed ≤6 months before enrollment; 73% were stage IV at initial diagnosis; 73% had prior bone marrow involvement; 92% had ECOG performance status ≤1; 85% were refractory and 12% were intolerant to bortezomib. Median duration of exposure to everolimus was 58 days (range, 13–221). Efficacy analysis of best overall disease response revealed no CR, 3 PR (12%), 14 SD (54%), 3 PD (12%), and 6 unknown (23%). ORR (CR+PR) was 12% (95% CI, 2–30) and met the requirement for full recruitment in Stage 2 of the study ahead of the Stage 1 enrollment target. A total of 19 patients discontinued from the study, 7 (27%) due to adverse events, 9 (35%) due to PD, and 3 (12%) withdrew consent. In the safety analysis, grade 3 or 4 adverse events suspected to be related to study treatment in ≥2 patients (>7%) were anemia, thrombocytopenia (including 1 grade 4), diarrhea, hyperglycemia (including 1 grade 4), and pneumonitis. Conclusion: Early analysis from this ongoing phase II study (stage I) shows that oral everolimus 10 mg/d has promising single-agent activity with 12% PR and 54% SD and good tolerability in bortezomib-refractory and intolerant MCL. The efficacy results support continuing to stage II enrolling more patients into this study. Disclosures: O'Connor: SAB-Pharma: Research Funding. Winter:Novartis Pharmaceuticals: Consultancy, Research Funding. Yuan:Novartis Pharmaceuticals: Employment, Equity Ownership. Robeva:Novartis Pharmaceuticals: Employment, Equity Ownership. Cauwel:Novartis Pharmaceuticals: Employment, Equity Ownership. Chau:Novartis Pharmaceuticals: Employment, Equity Ownership. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding.

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