Phase I study of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in patients with metastatic pancreatic ductal adenocarcinoma (PDAC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS4671-TPS4671 ◽  
Author(s):  
Andrew L. Coveler ◽  
David Lawrence Bajor ◽  
Ashiq Masood ◽  
Emrullah Yilmaz ◽  
Anthony Frank Shields ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Primary Objective ◽  
Ductal Adenocarcinoma ◽  
Standard Regimen ◽  
Prior Therapy ◽  
Igg1 Monoclonal Antibody ◽  
Duration Of Response ◽  
Antigen Presenting

TPS4671 Background: SEA-CD40 is an investigational non-fucosylated, humanized IgG1 monoclonal antibody directed against CD40, a co-stimulatory receptor expressed on antigen-presenting cells (APCs). Activation of CD40 on APCs upregulates cytokine production and co-stimulatory receptors, enhancing tumor antigen presentation to T cells. Preclinical data indicate that treatment of PDAC with chemotherapy in conjunction with a CD40 agonist could enhance antigen presentation and initiate an antitumor immune response (Byrne KT and Vonderheide RH, Cell Rep 2016;15, 2719–32). An ongoing Phase 1 study (SGNS40-001) is evaluating SEA-CD40 as monotherapy and in combination with pembrolizumab in patients with advanced solid or hematologic malignancies. A new cohort is enrolling to evaluate the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in PDAC. Methods: The cohort consists of patients with metastatic PDAC who have had no prior therapy for metastatic disease. Patients must be ≥18 years old, with (neo)adjuvant therapy completed >4 months prior to enrollment, ECOG status ≤1, adequate renal, hepatic, and hematologic function, and measurable disease per RECIST v 1.1 criteria. A standard regimen of gemcitabine and nab-paclitaxel on Days 1, 8, and 15 of each 28-day cycle is administered with SEA-CD40 IV on Day 3. Pembrolizumab is administered every 42 days starting on Day 8. The primary objective is antitumor activity; secondary objectives are safety and tolerability and SEA-CD40 and pembrolizumab pharmacokinetics. Efficacy endpoints are confirmed RECIST ORR per investigator (primary), disease control rate (response or stable disease ≥16 weeks), duration of response, PFS, and OS. Disease is assessed every 8 weeks using RECIST and immune-based RECIST (iRECIST). Treatment continues until occurrence of unacceptable toxicity, progressive disease per iRECIST, consent withdrawal, or study closure. Assessment of dose-limiting toxicity will occur initially in groups of 6 patients to identify the recommended phase 2 dose of SEA-CD40 for the cohort. Enrollment to this cohort began in November 2019. Clinical trial information: NCT02376699 .

Phase I study of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in patients (pts) with metastatic pancreatic ductal adenocarcinoma (PDAC) (trial in progress).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS451-TPS451
Author(s):  
David Lawrence Bajor ◽  
Martin Gutierrez ◽  
Gina M. Vaccaro ◽  
Ashiq Masood ◽  
Ursa Abigail Brown-Glaberman ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Hematologic Malignancies ◽  
Primary Objective ◽  
Ductal Adenocarcinoma ◽  
Standard Regimen ◽  
Prior Therapy ◽  
Duration Of Response

TPS451 Background: SEA-CD40 is an investigational non-fucosylated, humanized IgG1 monoclonal antibody directed against CD40, a co-stimulatory receptor expressed on antigen-presenting cells (APCs). Activation of CD40 on APCs upregulates cytokine production and co-stimulatory receptors, enhancing tumor antigen presentation to T cells. Preclinical data indicate that treatment of PDAC with chemotherapy in conjunction with a CD40 agonist could enhance antigen presentation and initiate an antitumor immune response (Byrne KT and Vonderheide RH, Cell Rep 2016;15, 2719–2732). A Phase 1 study (SGNS40-001) is evaluating SEA-CD40 monotherapy and in combination with other agents in pts with advanced solid or hematologic malignancies. A cohort is enrolling to evaluate the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in PDAC. Methods: The cohort consists of pts with metastatic PDAC who have had no prior therapy for metastatic disease. Pts must be ≥18 years old, with (neo)adjuvant therapy completed > 4 months prior to enrollment; ECOG status ≤1; adequate renal, hepatic, and hematologic function; and measurable disease per RECIST v 1.1 criteria. A standard regimen of gemcitabine and nab-paclitaxel on Days 1, 8, and 15 of each 28-day cycle is administered with SEA-CD40 IV on Day 3. Pembrolizumab is administered every 42 days starting on Day 8. The primary objective is to evaluate antitumor activity; secondary objectives are to evaluate safety and tolerability and SEA-CD40 and pembrolizumab pharmacokinetics. Efficacy endpoints are confirmed RECIST objective response rate per investigator (primary), disease control rate (response or stable disease ≥16 weeks), duration of response, progression-free survival, and overall survival. Disease is assessed every 8 weeks using RECIST and immune-based RECIST (iRECIST). Treatment continues until unacceptable toxicity, progressive disease per iRECIST, consent withdrawal, or study closure, whichever occurs first. Assessment of dose-limiting toxicity will occur initially in groups of 6 pts to identify the recommended phase 2 dose of SEA-CD40 for the cohort. Enrollment to this cohort began in November 2019. Clinical trial information: NCT02376699.

A multicenter phase I study of cabazitaxel, mitoxantrone, and prednisone for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 202-202 ◽  
Author(s):  
Mallika Sachdev Dhawan ◽  
Mina Lee ◽  
Alan H. Bryce ◽  
Vivian K. Weinberg ◽  
Charles J. Ryan ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase 1 ◽  
Single Agent ◽  
Median Number ◽  
Primary Objective ◽  
Hematologic Toxicity ◽  
Castration Resistant Prostate Cancer ◽  
Multicenter Phase ◽  
Duration Of Response ◽  
Number Of Treatment

202 Background: Cabazitaxel and prednisone (Cbz/pred) extend survival in mCRPC patients (pts) following docetaxel and first-line studies comparing Cbz to docetaxel are ongoing. Mito/pred also has anti-tumor activity in mCRPC and a non-overlapping mechanism of action and toxicity profile with Cbz. A multicenter phase 1 trial was initiated to establish the maximally tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of Cbz, Mito, and Pred(CAMP). Methods: Chemotherapy (chemo)-naive pts with mCRPC were enrolled in an accelerated titration design. The primary objective was to determine the MTD and RP2D of CAMP; secondary objectives included PSA response rate and duration of response. Cbz 20 and 25 mg/m2 were evaluated in combination with escalating doses of Mito (starting dose 4 mg/m2), both administered on day 1 of a 21-day cycle. Pred 5 mg BID and pegfilgrastim were given with each cycle. Results: 23 pts were enrolled. The median age was 66 (range 51-78) and the median baseline PSA was 62.5 (range 3-791.2). There were 2 DLTs (sepsis and febrile neutropenia) observed at the dose level of Cbz 25 mg/m2 + Mito 10 mg/m2 (n = 4). There was 1 DLT (febrile neutropenia) observed with Cbz 20 mg/m2 (N = 12), establishing Cbz 20 mg/m2 + Mito 12 mg/m2 as the MTD and RP2D. The most common grade ³ 3 related adverse events were hematologic (neutropenia, n = 9; thrombocytopenia, n = 3; febrile neutropenia, n = 3). The median number of treatment cycles was 7.5 (range 2-16), and 2 pts remain on study. Greater than or equal to 50% maximal PSA declines from baseline were observed in 12 of 19 evaluable pts(63%). The median duration of response has not been reached (range 4.9-10.0+ months). Conclusions: The approved single-agent dose of Mito (12 mg/m2) was safely combined with Cbz 20 mg/m2, a dose with demonstrated activity in mCRPC and potentially less hematologic toxicity than 25 mg/m2. Preliminary efficacy data are encouraging with durable control of disease observed in a subset of pts. Further study of the treatment combination is warranted. Clinical trial information: NCT01594918.

scholarly journals A Phase 1 Study of the BET-Bromodomain Inhibitor OTX015 in Patients with Non-Leukemic Hematologic Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4417-4417 ◽  
Author(s):  
Catherine Thieblemont ◽  
Anastasios Stathis ◽  
Giorgio Inghirami ◽  
Lionel Karlin ◽  
Franck Morschhauser ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Research Funding ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Factor Vii ◽  
Significant Activity ◽  
Prior Therapy ◽  
Grade 3 ◽  
Dose Levels

Abstract Rationale: BET-bromodomain (BRD) proteins are DNA readers that bind acetylated histone (H) tails preferentially at hyperacetylated superenhancer promoter regions and trigger gene transcription. The expression of several oncogenes, including c-MYC, is epigenetically regulated by BRD. OTX015 is a BRD 2, 3 and 4 inhibitor that prevents BRD binding to acetylated H4 and downregulates gene expression of BRD-dependent genes. OTX015 has been shown to inhibit the growth of diffuse large B-cell lymphoma (DLBCL) cells in vitroand in animal models. Patients & Methods: Patients with non-leukemic hematologic malignancies refractory or resistant to standard therapies were enrolled in an ongoing phase 1 clinical study. Lymphoma patients had to have failed at least two lines of systemic therapy and have evaluable disease. OTX015 was given orally daily (QD) without a planned rest period, with 3-week cycles (cy). Successive cohorts of 3-6 patients were treated at increasing dose levels (DL) from 10 to 120 mg QD to determine the maximum tolerated dose (MTD) or the biologically optimal dose. A BID schedule was tested at DL 4 (40 mg x 2). Pharmacokinetics was assessed on day 1 and residual concentrations were measured on days 2, 8 and 15. Lymphoma assessment was performed according to Cheson’s criteria every 6-8 weeks. Results: From January 2013 to June 2014, 37 non-leukemic patients (18 DLBCL, 9 other lymphomas, 10 myeloma) were treated over 5 dose levels, 33 of whom were evaluable for dose limiting toxicity (DLT). Median age was 67 years (range 27-83), 22 patients were male, 27 patients had ECOG 0-1. Patients had a median of 4 prior therapy lines (range 2-8), including 10 patients with autologous stem cell transplantation. The median number of OTX015 cycles administered was 2 (range 1-10+). No DLTs were observed through DL4 (80 mg QD). Asymptomatic and rapidly reversible grade 4 thrombocytopenia was the DLT at DL4 BID (40 mg x2) and 120 mg QD continuous. Sixteen patients experienced grade 3-4 thrombocytopenia and 3 patients had asymptomatic grade 3-4 neutropenia. Grade 3 non-hematologic toxicities were diarrhea, vomiting, hyperglycemia, and hypernatremia (1 patient each). Other toxicities were non-cumulative grade 1-2 gastrointestinal events (8 patients with diarrhea, 3 dysgueusia, 2 vomiting, 1 nausea, 1 anorexia, 1 abdominal pain), hyperglycemia (7 patients), skin rash (3 patients), asymptomatic coagulation factor VII decrease (2 patients), and direct bilirubin increase (1 patient). Dose proportional plasma concentrations were observed and trough concentrations > 500 nM occurred regularly from 80 mg/day. Additional patients are currently being treated at 80 mg QD or with various discontinuous schedules at 120 mg (5 days on/2 days off, 2 weeks on/1 week off, 1 week on/2 weeks off) to determine the recommended regimen. Clinically relevant activity was reported in 6 patients treated from 40 to 120 mg, including one CR (120 mg, 17+ weeks [wks]) and 1 PR (80 mg, 28 wks), both in DLBCL patients failing 3-4 prior therapy lines, and both with clinical benefit. Four other patients (two with DLBCL, one follicular, and one lymphoplasmacytic lymphoma) had minor tumor shrinkage with clinical benefit (40 mg, 36+ wks; 80 mg, 14 wks; 120 mg 15 wks; 120 mg, 17 wks). Conclusions: OTX015 single agent exhibits clinically significant activity against resistant DLBCL with two responses and two minor tumor shrinkages among nine evaluable patients treated at doses ≥ 80 mg. Centralized pathology review including immunohistochemistry profiling is being performed retrospectively, and will be prospective in a DLBCL expansion cohort. Updated data including recommended regimen and correlations between clinical activity and biomarkers will be presented. Disclosures Thieblemont: Oncoethix SA: Research Funding. Stathis:Oncoethix SA: Research Funding. Inghirami:Oncoethix SA: Research Funding. Karlin:Oncoethix SA: Research Funding. Morschhauser:Oncoethix SA: Research Funding. Gleeson:Oncoethix SA: Research Funding. Broussais:Oncoethix SA: Research Funding. Amorim:Oncoethix SA: Research Funding. Salles:Oncoethix SA: Research Funding. Facon:Oncoethix SA: Research Funding. Cunningham:Oncoethix SA: Research Funding. Vey:Oncoethix SA: Research Funding. Bourdel:Oncoethix SA: Employee of study CRO Other. Herait:Oncoethix SA: CMO and Shareholder Other. Zucca:Oncoethix SA: Research Funding.

PX-171–004, a multicenter phase II study of carfilzomib (CFZ) in patients with relapsed myeloma: An efficacy update

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8537-8537 ◽  
Author(s):  
R. Vij ◽  
M. Wang ◽  
R. Orlowski ◽  
A. K. Stewart ◽  
S. Jagannath ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
Durable Response ◽  
Prior Therapy ◽  
Duration Of Response ◽  
Secondary Endpoints ◽  
Relapsed Disease

8537 Background: Carfilzomib (CFZ) is a proteasome inhibitor, active against hematologic malignancies. Preclinically, CFZ overcomes bortezomib (BTZ) resistance in multiple tumors, including myeloma (MM). PX-171–004 is an ongoing Phase II study evaluating safety and efficacy of CFZ in MM patients with relapsed disease after 1–3 prior therapies. Overall Response Rate (ORR) of 35.5% for all subjects was previously reported (ASH 2008); updated data are now available. Methods: Patients were divided into two cohorts: BTZ-naïve and BTZ-exposed. CFZ 20 mg/m2 was administered Days 1, 2, 8, 9, 15 and 16 in a 28-day cycle, for up to 12 cycles. Dexamethasone 4 mg po was administered prior to each dose in Cycle 1. The primary endpoint was ORR, defined as Partial Response (PR) or better. Secondary endpoints included Duration Of Response (DOR) and Time To Progression (TTP). Results: 31 patients were enrolled; 14 (45%) BTZ-naïve and 17 (55%) BTZ-exposed. Of the BTZ-exposed cohort, 2 subjects received BTZ exclusively as a single agent, 6 had BTZ in a chemotherapy combination, and 9 received BTZ in a transplant regime. Overall, 23 (74%) subjects had > 1 prior therapy and 27 (87%) received transplant. In BTZ-naïve patients, CFZ achieved an ORR of 57%; median DOR of 8.6 mos (range >1.9 to >9.7 mos). To date, 7 patients (50%) remain progression free and 3 patients have completed 12 cycles. The median follow-up was 10 mos and the median TTP has not been reached. For the BTZ- exposed group, CFZ achieved an ORR of 18%; median DOR not yet reached (>8.5 mos) (range >1 d to >8.5 mos). 7 patients (41%) are progression free and 3 patients have completed 12 cycles. Median follow-up and TTP were 9.2 and 8.9 mos, respectively. Conclusions: These preliminary results demonstrate that single-agent CFZ is tolerable for at least 1 yr and achieves sustained responses in relapsed MM. Prior BTZ mono/combination therapy does not preclude durable response with CFZ. These data support continuing evaluation of CFZ in the treatment of relapsed MM. [Table: see text] [Table: see text]

Pembrolizumab (pembro) plus low-dose ipilimumab (ipi) for patients (pts) with advanced renal cell carcinoma (RCC): Phase 1 KEYNOTE-029 study.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 510-510 ◽  
Author(s):  
Toni K. Choueiri ◽  
F. Stephen Hodi ◽  
John A. Thompson ◽  
David F. McDermott ◽  
Wen-Jen Hwu ◽  
...  
Keyword(s):  
Low Dose ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Pegylated Interferon ◽  
Prior Therapy ◽  
End Point ◽  
Duration Of Response ◽  
Report Data ◽  
Grade 3 ◽  
Ecog Ps

510 Background: The CTLA-4 antibody ipi and the PD-1 antibody pembro have demonstrated efficacy in pts with advanced malignancies. While these immune checkpoint inhibitors have shown robust activity as monotherapy, combination therapy may further improve outcomes. KEYNOTE-029 (NCT02089685) is a phase 1/2 study designed to assess the safety and efficacy of pembro + ipi or pegylated interferon alfa-2b (IFN-α) in pts with advanced melanoma or RCC. Here we report data from the phase 1 portion of the study in pts with RCC treated with pembro + ipi. Methods: Pts ≥18 years with advanced/unresectable or metastatic clear cell RCC who received ≥1 prior therapy for metastatic disease, had ≥1 measurable lesion per RECIST v1.1, and ECOG PS 0-1 were enrolled. Pts received pembro 2 mg/kg Q3W + low-dose ipi (1 mg/kg Q3W for 4 doses) until disease progression, unacceptable toxicity, investigator/patient decision, or 2 years of pembro treatment. AEs were monitored throughout treatment and for 30 days thereafter and graded per NCI CTCAE v4.0. Primary end point was safety; primary efficacy end point was ORR assessed per RECIST v1.1 by independent central imaging vendor review. Results: As of the March 17, 2016, data cutoff, 10 pts with RCC received pembro + low-dose ipi. 60% were male, 70% were white, median age was 61 years (range, 48-70 years), 40% received 2 prior lines of therapy, and 40% received prior immunotherapy. With a median follow-up of 17.4 months (0.9-23.5 months), 70% of pts experienced treatment-related AEs (TRAEs) of any grade, most commonly fatigue (30%); and 50% experienced grade 3/4 TRAEs, most commonly increased lipase (20%). 50% of pts discontinued pembro because of TRAEs, most commonly increased lipase (40%). There were no treatment-related deaths. ORR was 20% (2 partial responses); median duration of response was not reached (14.1+-17.1 months+). An additional 3 pts had stable disease; disease control rate was 50%. Conclusions: The combination of pembro + low-dose ipi for 4 doses, followed by pembro monotherapy, demonstrates a manageable toxicity profile and preliminary antitumor activity in pts with advanced RCC. Clinical trial information: NCT02089685.

Randomized Phase III Study of FOLFOX Alone and with Pegilodecakin as Second-line Therapy in Patients with Metastatic Pancreatic Cancer (SEQUOIA).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 637-637 ◽  
Author(s):  
J. Randolph Hecht ◽  
Sara Lonardi ◽  
Johanna C. Bendell ◽  
Hao-Wen Sim ◽  
Teresa Macarulla ◽  
...  
Keyword(s):  
Phase 1 ◽  
Primary Objective ◽  
Phase Iii ◽  
Ductal Adenocarcinoma ◽  
Second Line Therapy ◽  
Phase 3 ◽  
Prior Surgery ◽  
Phase Iii Study ◽  
Grade 3 ◽  
Clinical Trial Information

637 Background: Effective therapies are limited for advanced metastatic pancreatic ductal adenocarcinoma (PDAC) patients (pts) who have progressed after 1st line gemcitabine-based chemotherapy (Gem). FOLFOX has clinical benefit in Gem-refractory PDAC pts. A phase 1 trial demonstrated promising activity with pegilodecakin (PEG; pegylated IL-10) and FOLFOX in Gem-refractory PDAC pts, providing rationale for the phase 3 trial (SEQUOIA; NCT02923921). Methods: SEQUOIA is a randomized phase 3 study of FOLFOX alone or with PEG in Gem-refractory PDAC pts. Pts were randomized 1:1, excluding pts with prior surgery and radiation, and received FOLFOX ( dI-Leucovorin [400 mg/m2], oxaliplatin [85 mg/m2] followed by bolus 5-FU [400 mg/m2], and a 46-48 hr infusion of 5-FU [2400 mg/m2]) on day 1 of a 14-day cycle up to 12 cycles. PEG + FOLFOX arm received PEG (0.4 mg/d if ≤80kg and 0.8mg/d if > 80 kg) on Days 1-5 then Days 8-12 + FOLFOX. Pts could continue PEG monotherapy (0.8mg/d if ≤ 80 kg and 1.6 mg/d if > 80 kg) after FOLFOX discontinuation. Primary objective was OS. Secondary objectives included PFS, ORR per RECIST 1.1, and safety. Assuming OS HR of 0.74, the study was powered to 85% at 2-sided α = 0.05 with ~566 pts to detect superiority of PEG + FOLFOX. Results: As of Sept 9, 2019, 567 pts were randomized to PEG + FOLFOX (283) or FOLFOX (284). The majority (94.7%) had 1st line Gem+nab paclitaxel. The mOS was similar between FOLFOX + PEG arm [5.8 months] and FOLFOX arm [6.3 months] with HR = 1.045 (95% CI [0.863, 1.265], p = 0.6565). No statistical difference was observed for PFS, mPFS was 2.1 months in both arms with HR = 0.981, (95% CI [0.808, 1.190], p = 0.8144). ORR was 4.6% on the PEG+FOLFOX arm and 5.6% on the FOLFOX arm. Grade ≥3 adverse events that were 5% higher on the PEG+FOLFOX arm included thrombocytopenia (25.2% vs. 3.6%), anemia (16.2% vs. 4.0%), neutropenia (29.5% vs. 22.7%), and fatigue (17.6% vs. 10.8%). Conclusions: The addition of PEG to FOLFOX did not improve efficacy (OS, PFS, ORR) in advanced PDAC pts who have progressed after 1st line Gem-containing therapy. Safety findings were consistent with previous data observed from PEG + chemotherapy; toxicity was manageable and tolerable. Clinical trial information: NCT02923921.

Malignant glioma subset from Actuate 1801: A phase 1/2 study of 9-ING-41, a glycogen synthase kinase 3 beta (GSK-3β) inhibitor, as a single agent and combined with chemotherapy, in patients with refractory hematologic malignancies or solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2051-2051
Author(s):  
Yazmin Odia ◽  
Ludimila Cavalcante ◽  
Howard Safran ◽  
Steven Francis Powell ◽  
Pamela N. Munster ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Phase 1 ◽  
Single Agent ◽  
Human Study ◽  
Chemotherapy Resistance ◽  
Hematologic Malignancies ◽  
Primary Objective ◽  
Diffuse Astrocytoma ◽  
Mgmt Promoter ◽  
Gsk 3Β

2051 Background: GSK-3β, a serine/threonine kinase, is a key regulator of metabolism and glycogen biosynthesis. GSK-3β aberrant overexpression promotes tumor progression and chemotherapy resistance through NF-κB and p53-mediated apoptotic pathways. GSK-3β inhibition impacts immunomodulation through downregulation of checkpoints, such as PD-L1 and LAG-3, and increasing NK and T-cell mediated killing of tumor cells. 9-ING-41 is a small-molecule potent selective GSK-3β inhibitor with preclinical antitumor activity against several tumor types. In chemoresistant PDX models of glioblastoma (GBM), 9-ING-41 enhanced the antitumor effect of CCNU and CPT-11. Methods: In the first-in-human study (NCT03678883), patients (pts) with refractory malignancies received 9-ING-41 monotherapy (n = 65) or in combination with one of 8 cytotoxic regimens after prior treatment with the same chemotherapy (n = 162). We report the subset of pts with recurrent gliomas treated with 9-ING-41 monotherapy IV twice a week in 21-day cycles at different dose levels (3.3, 5, 9.3, 15mg/kg), or in combination with lomustine 30 mg/m² orally once weekly in 84-day cycles. Primary objective was safety and tolerability. Results: An RP2D of 15mg/kg IV was confirmed across all 9 regimens, no accentuation of chemotherapy-related toxicity noted. Of 18 glioma patients enrolled, 13 were GBM, 2 anaplastic astrocytomas, 1 diffuse astrocytoma, and 1 anaplastic oligodendroglioma. Four patients received single agent 9-ING-41, 14 treated concurrently with lomustine. Demographics: 6 female, 12 male; median age 52 (30-69) years; median ECOG was 1 (0-2). All received first-line radiation and temozolomide (18/18), prior therapies for recurrences included nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), immune checkpoint inhibitor (4/18). Median recurrences 3 (1-6). Genomic alterations from available NGS reports included: IDH WT (11), IDH mutation (3), MGMT promoter unmethylated (11), MGMT promoter methylated (1), 1p19q co-deletion (10), EGFR amplification (6), EGFR v3 mutation (3), TERT promoter mutation (6), PTEN loss (3), NF1 rearrangement (2), ATRX loss (2), TP53 mutated (4), CDKN2A deletion (2), RB1 loss (1), PALB-2 mutation (10). No SAEs or grade 3/4 AEs attributed to 9-ING-41 were noted; AEs included G1/2 transient vision changes (9/18, 50%), infusion reactions (4/18, 22%). Side effects from lomustine included: G3/4 thrombocytopenia (3/14, 21%), and G1/2 fatigue (4/14, 28%). Best overall response: 1 minimal response (-43%) after 2 cycles of 9-ING-41 and lomustine. Median days on therapy was 55 (4-305), 4/18 (22%) were stable for 20 weeks or longer. Conclusions: These results show 9-ING-41 alone or in combination is safe and warrants further study in glioma patients. Clinical trial information: NCT03678883.

Pralatrexate Induces Responses in Patients with Highly Refractory Peripheral T-Cell Lymphoma (PTCL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1678-1678 ◽  
Author(s):  
Kerry J. Savage ◽  
Andrei R. Shustov ◽  
Andre Goy ◽  
Steven M. Horwitz ◽  
Barbara Pro ◽  
...  
Keyword(s):  
Combination Chemotherapy ◽  
Research Funding ◽  
International Workshop ◽  
Phase 1 ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
Median Number ◽  
Folic Acid Supplementation ◽  
Refractory Disease ◽  
Prior Therapy

Abstract Abstract 1678 Poster Board I-704 Background The outcome of patients with PTCL is poor and the majority of patients ultimately have refractory disease to a variety of agents, including standard therapy with CHOP or CHOP-like regimens. Pralatrexate is a rationally designed antifolate that has a high affinity for the reduced folate carrier-1 (RFC-1) and is likely to be retained longer within cancer cells due to efficient polyglutamation by folylpolyglutamyl synthetase. Phase 1 and 2 clinical trials have shown that pralatrexate is safe and active in hematologic malignancies including relapsed or refractory PTCL (O'Connor OA, JCO 2009:10.1200/JCO.2008.20.8470). The PROPEL study, a pivotal, international, Phase 2 single-arm trial, evaluated pralatrexate in patients with relapsed or refractory PTCL who had a median of 3 prior therapies. Pralatrexate treatment was well tolerated and showed an overall response rate of 28% (30/109 patients) by central independent review. The objective of this current analysis was to characterize the treatment response among patients who were considered to have refractory disease, defined as showing 1) no evidence of response to their most recent prior therapy or 2) no evidence of response to all prior therapies. Methods Patients received pralatrexate 30 mg/m2 once weekly for 6 weeks in 7-week cycles, with vitamin B12 and folic acid supplementation. Response to pralatrexate was assessed after each odd-numbered treatment cycle and was based on rigorous centralized review of imaging and clinical data using the International Workshop Criteria (Cheson BD, JCO 1999;17:1244). Results The most commonly used prior therapies were CHOP-based chemotherapy (70%), platinum-based multi-agent chemotherapy (41%), and non-platinum containing combination chemotherapy (39%). Eighteen (16%) patients received autologous stem-cell transplantation (SCT) prior to the PROPEL study. Of the 109 patients who were evaluable for response, 69 (63%) patients had no evidence of response to the most recent therapy and 26 (25%) patients had had no evidence of response to any therapy. The ORR for the 69 patients with no evidence of response to their most recent prior therapy was 25% (n=17) according to central review and 36% (n=25) according to investigator review. The median duration of response was 99 days (range, 41-535) by central review. The median number of prior systemic therapies for these 69 patients was 3 (range, 1-11). Twenty-six patients had no evidence of response to any prior therapy before initiating pralatrexate, having received a median of 2.5 prior therapies (range, 1-7). Five (19%) of these patients responded to pralatrexate by central review and 7 (27%) responded by investigator review. The duration of centrally reviewed response to pralatrexate in the patients with no evidence of response to any prior therapy was 54, 57, 69, 78, and 306 days. Conclusions Pralatrexate has demonstrated activity in patients with PTCL who were refractory to their most recent therapy, including patients who were refractory to all prior therapies. Responses to pralatrexate were observed in patients with disease that was refractory to a range of therapies used in PTCL, including SCT and a variety of single agent and combination chemotherapy regimens, suggesting that pralatrexate can overcome mechanisms of drug resistance in this population. Disclosures Savage: Allos Therapeutics, Inc.: Consultancy, Honoraria. Horwitz:Allos Therapeutics, Inc: Consultancy, Research Funding. Pro:Allos Therapeutics, Inc.: Research Funding. Fruchtman:Allos Therapeutics, Inc.: Employment.

Role of capmatinib in MET exon 14-mutated advanced non-small cell lung cancer (NSCLC): A systematic review.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21150-e21150
Author(s):  
Israr Khan ◽  
Faiza Ahmed ◽  
Nazma Hanif ◽  
Mobeen Zaka Haider ◽  
Farhan Khalid ◽  
...  
Keyword(s):  
Phase 1 ◽  
Progression Free Survival ◽  
Cochrane Library ◽  
Tolerability Profile ◽  
Prior Therapy ◽  
Duration Of Response ◽  
Long Term Follow Up ◽  
Treatment Naïve ◽  
Elevated Creatinine ◽  
Line Of Therapy

e21150 Background: Capmatinib is a selective inhibitor of MET receptor that got accelerated FDA approval in May 2020 to treat NSCLC with MET ex 14 mutation (METex14). Here, we proclaim the first review of capmatinib efficacy and safety profile in METex14 positive NSCLC patients. Methods: A systematic literature search was conducted using PubMed, Cochrane Library, Clinicaltrials.gov, and Google Scholar. We compiled and analyzed the original studies evaluating the clinical response of capmatinib in MET ex14 mutated advanced NSCLC. Results: The most recent results (as of January 6, 2020) of the GEOMETRY Mono-1 phase 2 study showed an overall response rate (ORR) of 41% (69/97; 95% CI, 29-53) with 41% partial response (PR), and 36% stable disease (SD) in patients who previously received 1-2 prior therapy lines (cohort 4). While the ORR, PR, and SD were 68% ( n = 29/97; 95% CI, 48-84), 64%, and 25%, respectively in treatment naïve patients (cohort 5b). Median progression-free survival (mPFS) and duration of response (DOR) were 5.4 months (mon) and 9.7 mon (95%CI, 5.6-13.0) in cohort 4 vs. 12.4 mon and 12.6 mon (CI, 5.6- not estimated), respectively in cohort 5b. Moreover, disease control was shown in n = 54/69 patients in cohort 4 (95% CI 78 (97-87) and n = 27/28 patients (95% CI 96 (82-100). A post-hoc analysis of 19 patients out of 69 who were pre-treated with immunotherapy demonstrated an ORR of 57.9% (n = 11/19; 95%CI 33.5-79.7) with capmatinib. In contrast, treatment-naive had an ORR of 34% (n = 17/50; 95%CI 21.2-48.8) as per the investigator. Median PFS was 3.29 mon noted on prior therapy. In the phase 1 retrospective analysis reported by Choi et al., ORR was 50% with a median duration of 16.1 (5.3-36.4) mon. Among 45 Japanese pts with MET ex 14 mutated or MET amplified status, the ORR was 36.4% (95% CI 10.9%-69.2%) with a PFS of 4.70 mon in the MET ex 14 mutated groups who had received a second or third line of therapy. Most commonly reported adverse events were peripheral edema, nausea, vomiting, and elevated creatinine across all studies and were mostly grade 1-2. Conclusions: Our results showed that capmatinib has promising anti-tumor activity in patients with NSCLC harboring MET exon 14 skipping mutation. The efficacy and tolerability profile of capmatinib is remarkable, particularly in treatment-naïve patients. Although the GEOMETRY Mono-1 trial is still ongoing, further clinical studies with long-term follow-up are needed.

A multicenter phase I study of cabazitaxel (Cbz), mitoxantrone (Mito), and prednisone (Pred) (CAMP) for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC).

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 238-238 ◽  
Author(s):  
Rahul Raj Aggarwal ◽  
Alan H. Bryce ◽  
Vivian K. Weinberg ◽  
Charles J. Ryan ◽  
Christina Louise Derleth ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Adverse Events ◽  
Phase 1 ◽  
Single Agent ◽  
Median Number ◽  
Primary Objective ◽  
Hematologic Toxicity ◽  
Castration Resistant Prostate Cancer ◽  
Multicenter Phase ◽  
Duration Of Response

238 Background: Cbz/pred extends survival in mCRPC patients (pts) following docetaxel and first-line studies comparing Cbz to docetaxel are ongoing. Mito/pred also has anti-tumor activity in mCRPC and a non-overlapping mechanism of action and toxicity profile with Cbz. A multicenter phase 1 trial was initiated through the DOD PCCTC to establish the maximally tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of Cbz, Mito, and Pred (CAMP). Methods: Chemotherapy (chemo)-naïve pts with mCRPC were enrolled in an accelerated titration design. The primary objective was to determine the MTD and RP2D of CAMP; secondary objectives included PSA response rate and duration of response. Cbz 20 and 25 mg/m2 were each evaluated in combination with escalating doses of Mito (starting dose 4 mg/m2), both administered on day 1 of a 21-day cycle. Pred 5 mg BID and pegfilgrastim were given with each cycle. Results: 20 pts were enrolled. The median age was 66 (range 51-78) and the median baseline PSA was 62.5 (range 3.0-791.2). There were 2 DLTs observed at the dose level of Cbz 25 mg/m2 + Mito 10 mg/m2 (sepsis and febrile neutropenia). No DLTs were observed with Cbz 20 mg/m2 (N = 10), establishing Cbz 20 mg/m2 + Mito 12 mg/m2 as the MTD and RP2D. The most common grade ≥ 3 related adverse events were hematologic (neutropenia, n = 8; thrombocytopenia, n = 3; febrile neutropenia, n = 2). No cardiac adverse events were observed. The median number of treatment cycles was 9 (range 2-16), and 5 pts remain on study. Greater than 50% maximal PSA declines from baseline were observed in 8 of 18 evaluable pts (44%). Objective tumor responses have been observed in 2 of 4 pts (50%) with measurable disease, with evaluation ongoing. The median duration of response has not been reached (range 4.9-10.0+ months). Conclusions: The approved single-agent dose of Mito (12 mg/m2) was safely combined with Cbz 20 mg/m2, a dose with demonstrated activity in mCRPC and potentially less hematologic toxicity than 25 mg/m2. Preliminary efficacy data are encouraging with durable responses observed in a subset of pts. Further study of the treatment combination is warranted. Clinical trial information: NCT01594918.

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