A dose-escalation phase I study of a first-in-class cancer stemness inhibitor in patients with advanced malignancies.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2542-2542 ◽  
Author(s):  
Adrian Langleben ◽  
Jeffrey G. Supko ◽  
Sebastien J. Hotte ◽  
Gerald Batist ◽  
Hal W. Hirte ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Cancer Stemness ◽  
Advanced Malignancies ◽  
Progression Of Disease ◽  
Excellent Safety Profile ◽  
Grade 3 ◽  
Anti Tumor Activity ◽  
Unacceptable Toxicity ◽  
Clinical Trial Information

2542 Background: Cancer Stem Cells (CSC) are considered to be fundamentally responsible for malignant growth, relapse, metastasis, and resistance to conventional therapies. BBI608 is an orally-administered first-in-class cancer stemness inhibitor which blocks CSC self-renewal and induces cell death in CSC as well as non-stem cancer cells by inhibition of the Stat3, Nanog and b-catenin pathways, and has shown potent anti-tumor and anti-metastatic activities pre-clinically. Methods: A phase 1 dose escalation studyin adult patients with advanced cancer who had failed standard therapies was conducted to determine the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics and preliminary anti-tumor activity of BBI608. A modified Simon accelerated titration scheme was used for dose escalation, with a cycle consisting of twice-daily oral administration of BBI608 for 4 weeks. Cycles were repeated every 4 weeks (28 days) until progression of disease, unacceptable toxicity, or other discontinuation criteria were met. Results: Fourteen cohorts (N=41) were dosed from 20 mg to 2000 mg/day with adverse events being generally mild; the most common being grade 1-2 diarrhea, nausea, anorexia and fatigue. Four grade 3 events included diarrhea (n=3) and fatigue (n=1). MTD was not reached and further dose escalation was limited by pill burden. By the 400 mg/day dose level the plasma concentration of BBI608 was sustained for over 8 hours at a concentration above 1.5 uM (several fold above the IC50). 17/26 patients evaluable for tumor response achieved SD, for a DCR of 65%. Prolonged TTP was observed in 12/26 evaluable patients (46%), including patients with colorectal (CRC), head and neck, gastric, ovarian, melanoma, and breast cancer. In the subset of patients with CRC (N=18), SD was seen in 8/12 evaluable (67%). A median PFS of 14 weeks and median OS of 47 weeks were observed in evaluable CRC patients. Conclusions: Dose escalation of BBI608, a first-in-class cancer stem cell pathway inhibitor, has been achieved without dose limiting toxicity. BBI608 has shown an excellent safety profile, favorable pharmacokinetics, and encouraging signs of clinical activity particularly in CRC Clinical trial information: NCT01775423.

Pharmacokinetics and safety of an oral ALK inhibitor, ASP3026, observed in a phase I dose escalation trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2602-2602 ◽  
Author(s):  
Amita Patnaik ◽  
Patricia LoRusso ◽  
Howard A. Ball ◽  
Erkut Bahceci ◽  
Geoffrey Yuen ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Expansion Phase ◽  
Advanced Malignancies ◽  
Grade 3 ◽  
Ecog Ps ◽  
Clinical Trial Information

2602 Background: ASP3026 (3026) is a selective, potent, ATP-competitive, small molecule oral inhibitor of ALK receptor tyrosine kinase that has not previously been tested in humans. A Phase 1 dose-escalation trial, using a 3+3 design, evaluating 3026 as an oral single agent was conducted to investigate PK (Day 1 and Day 28), safety and clinical activity in patients (pts) with advanced malignancies (excluding leukemias) of ECOG PS 2 or less. Methods: 3026 was administered under fasting conditions on a continuous schedule to pts in successive dose-escalating cohorts at doses ranging from 25 mg QD to 800 mg QD. Results: Thirty pts were enrolled into the dose escalation part of the study. The MTD was determined based on DLT data from cycle 1. Three DLTs were observed: grade 2 nausea and vomiting leading to dose reduction at 525 mg QD; grade 3 rash leading to dose reduction, and grade 3 ALT/AST increase leading to study withdrawal at 800 mg QD. The most common AEs were constipation, vomiting, diarrhea, nausea and abdominal pain, and all AEs were manageable and reversible. Median AUC and Cmax increased proportionally with dose from 25 mg QD to 800 mg QD. There was no evidence of non-linear PK at ASP3026 doses >25 mg QD. The median terminal half-life was approximately 10 - 41 hours. Overall, A3026 appears well absorbed with median Tmax around 3 hours for both Day 1 and Day 28. Terminal T1/2 appears adequate for one daily dosing with median values ranging from approximately 18 to 34 hours. Based on visual inspection of pre-dose (trough) values from Days 8, 15, 22, and 28 it appears that steady-state conditions are achieved by day 28. Conclusions: The MTD of 3026 is 525 mg QD. Treatment with 3026 resulted in a promising safety and PK profile in pts with advanced malignancies. Further evaluation of 3026 in pts with tumors harboring gene mutation or ALK fusion genes in the cohort expansion phase at the MTD is ongoing. Clinical trial information: NCT01401504.

scholarly journals Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer

2020 ◽  
Vol 38 (6) ◽  
pp. 1836-1845
Author(s):  
Shunsuke Kondo ◽  
Masaomi Tajimi ◽  
Tomohiko Funai ◽  
Koichi Inoue ◽  
Hiroya Asou ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Mammalian Target Of Rapamycin ◽  
Japanese Patients ◽  
Competitive Inhibitor ◽  
Primary Objective ◽  
Dose Escalation Study ◽  
Dual Inhibitor ◽  
Advanced Malignancies ◽  
Grade 3

Summary LY3023414 is an oral, selective adenosine triphosphate-competitive inhibitor of class I phosphatidylinositol 3-kinase isoforms, mammalian target of rapamycin, and DNA-protein kinase in clinical development. We report results of a 3 + 3 dose-escalation Phase 1 study for twice-daily (BID) dosing of LY3023414 monotherapy in Japanese patients with advanced malignancies. The primary objective was to evaluate tolerability and safety of LY3023414. Secondary objectives were to evaluate pharmacokinetics and to explore antitumor activity. A total of 12 patients were enrolled and received 150 mg (n = 3) or 200 mg (n = 9) LY3023414 BID. Dose-limiting toxicities were only reported at 200 mg LY3023414 for 2 patients with Grade 3 stomatitis. Common treatment-related adverse events (AEs) across both the dose levels included stomatitis (75.0%), nausea (66.7%), decreased appetite (58.3%), diarrhea, and decreased platelet count (41.7%), and they were mostly mild or moderate in severity. Related AEs Grade ≥ 3 reported for ≥1 patient included anemia, stomatitis, hypophosphatemia, and hyperglycemia (n = 2, 16.7%). Two patients discontinued due to AEs (interstitial lung disease and stomatitis). No fatal events were reported. The pharmacokinetic profile of LY3023414 was characterized by rapid absorption and elimination. Five patients had a best overall response of stable disease (150 mg, n = 3; 200 mg, n = 2) for a 55.6% disease control rate. LY3023414 up to 200 mg BID is tolerable and safe in Japanese patients with advanced malignancies.

A phase I study of the safety and pharmacokinetics of DNIB0600A, an anti-NaPi2b antibody-drug-conjugate (ADC), in patients (pts) with non− small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (OC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2507-2507 ◽  
Author(s):  
Michael S. Gordon ◽  
David E. Gerber ◽  
Jeffrey R. Infante ◽  
Jian Xu ◽  
David S. Shames ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Safety Data ◽  
Median Number ◽  
Antibody Drug Conjugate ◽  
Xenograft Models ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Dose Levels ◽  
Anti Tumor Activity ◽  
Clinical Trial Information

2507 Background: NaPi2b (SLC34A2) is a multi-transmembrane, sodium-dependent phosphate transporter expressed in non-squamous NSCLC and non-mucinous OC. DNIB0600A is an ADC consisting of a humanized IgG1 anti-NaPi2b monoclonal antibody and anti-mitotic agent, MMAE, that shows anti-proliferative activity in xenograft models. Methods: This study evaluated safety, pharmacokinetics, and pharmacodynamics of DNIB0600A (0.2-2.8 mg/kg) given every 3 weeks (q3w) to pts with NSCLC or OC. A traditional 3+3 design was used for dose escalation followed by expansion by disease at the recommended Phase 2 dose (RP2D). Tumor NaPi2b expression was evaluated in archival tissue. Anti-tumor activity was evaluated per RECIST 1.1. Results: As of 10 Dec 2012, 30 dose escalation pts have enrolled (16 NSCLC; 14 OC), median age 61 (range 45-78), PS 0-1, median number of prior regimens 5 (1-12), received a median of 3 (1-17) doses of DNIB0600A. No DLTs occurred at the maximum assessed dose of 2.8 mg/kg; enrollment in the expansion cohort at 2.4 mg/kg is ongoing. The most common related AEs regardless of Grade were fatigue (43%), decreased appetite (37%), nausea (30%), constipation, dysgeusia, vomiting, and peripheral neuropathy (each 17%), and diarrhea (13%). One pt at 1.8 mg/kg experienced a DLT (Grade 3 dyspnea), however, no additional DLTs occurred through the maximally administered dose of 2.8 mg/kg. Expansion at 2.4 mg/kg was selected based on totality of safety data. No accumulation of total antibody, free MMAE, or conjugated MMAE was observed. Exposure of each analyte was dose proportional. Approximately 70% of NSCLCs and 85% of OC expressed high levels (IHC 2+/3+) of NaPi2b. Of the 18 pts treated at dose levels 1.8-2.8 mg/kg (10 NSCLC; 8 OC) 3 pts had a confirmed partial response (PR) with response durations of 8.8+ (OC), 4.4+ (NSCLC), and 1.4+ (OC) months, censored at data cutoff, and 1 additional pt had an unconfirmed PR (OC). Dose expansion data will be presented. Conclusions: DNIB0600A administered q3w has an encouraging safety profile and evidence of anti-tumor activity in both NSCLC and OC. Further studies are planned. Clinical trial information: NCT01375842.

Cancer stemness inhibition and chemosensitization: Phase 1b/II study of cancer stemness inhibitor napabucasin (BBI-608) with FOLFIRI +/- bevacizumab (Bev) administered to colorectal cancer (CRC) patients (pts).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 593-593 ◽  
Author(s):  
Johanna C. Bendell ◽  
Bert H. O'Neil ◽  
Alexander Starodub ◽  
Derek J. Jonker ◽  
Thorvardur Ragnar Halfdanarson ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Stroma ◽  
Electrolyte Imbalance ◽  
Synergistic Activity ◽  
Cancer Stemness ◽  
Prior Therapy ◽  
Phase 1B ◽  
Grade 3 ◽  
Anti Tumor Activity ◽  
Clinical Trial Information

593 Background: Cancer stem cells or stemness-high cancer cells are considered to be fundamentally important for resistance to therapy, recurrence and metastasis. Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting Stat3-driven gene transcription. Preclinical studies suggest that napabucasin sensitizes heterogeneous cancer cells to chemotherapeutics and targeted agents. Methods: This study was performed to assess signs of anti-tumor activity of napabucasin in combination with FOLFIRI +/- Bev in CRC pts. Napabucasin was administered at 240 mg BID. FOLFIRI (5-FU 400 mg/m2 bolus with 2400 mg/m2, irinotecan 180 mg/m2, and leucovorin 400 mg/m2 infusion) +/- Bev 5 mg/kg was administered biweekly until disease progression or other discontinuation criterion. pSTAT3 status of archival tumor tissue was assayed by immunohistochemistry using the H-score with pSTAT3highdefined as ≥ 5% pSTAT3+ cancer cells and tumor stroma staining at ≥ 2+ intensity. Results: 63 CRC pts with an average of >2 prior therapy lines were enrolled. No pharmacokinetic interactions or dose-limiting toxicity was observed. Most common adverse events (AEs) included grade 1/2 diarrhea, nausea, vomiting and fatigue. 25 pts had grade 3 AEs, including diarrhea (14), fatigue (4), dehydration (2), electrolyte imbalance (4), nausea (1) and weight loss (1) resolved with dose reduction and supportive care. Among 63 pts enrolled who received RECIST evaluation, disease control (CR+PR+SD) was observed in 49 pts (86%) with an overall response (CR+PR) of 28% with 1 pt achieving CR. Clinical trial information: NCT02024607. Conclusions: This phase Ib/II study suggests napabucasin may sensitize chemorefractory CRC to FOLFIRI +/- Bev. Encouraging signs of synergistic activity between napabucasin and FOLFIRI was observed in CRC pts regardless of pSTAT3 status.[Table: see text]

Phase II study of ibrutinib in advanced carcinoid and pancreatic neuroendocrine tumors.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 434-434
Author(s):  
Taymeyah E. Al-Toubah ◽  
Tiffany Valone ◽  
Michael J. Schell ◽  
Jonathan R. Strosberg
Keyword(s):  
Neuroendocrine Tumors ◽  
Phase Ii ◽  
Objective Response ◽  
Prior Therapy ◽  
Progression Of Disease ◽  
Prospective Phase ◽  
Well Differentiated ◽  
Grade 3 ◽  
Unacceptable Toxicity ◽  
Clinical Trial Information

434 Background: Ibrutinib is an orally administered, inhibitor of Bruton’s tyrosine kinase (Btk). Preclinical data suggest that mast cells are recruited with neuroendocrine tumors (NETs) where they remodel the stroma and stimulate angiogenesis, driving macroscopic tumor expansion. Ibrutinib inhibits mast cell degranulation, and has been associated with regression of a mouse insulinoma model. Methods: A prospective, phase II trial evaluated patients with advanced GI/lung NETs and pNETs who had evidence of progression within 12 months of study entry on at least one prior therapy. Patients received ibrutinib 560mg daily until unacceptable toxicity, progression of disease, or withdrawal of consent. Primary endpoint was objective response rate. Results: 20 patients were enrolled on protocol from November 2015 – December 2017 (15 carcinoid and five pNETs). No patients experienced objective response. Median PFS was 3.1 months. A total of 43 drug related AEs were captured as probably or definitely associated with ibrutinib. Five patients experienced probably or definitely related grade 3 AEs and one patient experienced a probably related grade 4 AE. Five patients discontinued treatment prior to radiographic assessment. Conclusions: Ibrutinib does not show significant evidence of activity when compared to other agents (e.g. Everolimus) in well-differentiated gastroenteropancreatic and lung NETs. Clinical trial information: 02575300.

Immune checkpoint inhibition (ICI) in combination with SBRT in patients with advanced pancreatic adenocarcinoma (aPDAC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 192-192 ◽  
Author(s):  
Gagandeep Brar ◽  
Changqing Xie ◽  
Charalampos S. Floudas ◽  
M. Pia Morelli ◽  
Suzanne Fioravanti ◽  
...  
Keyword(s):  
Partial Response ◽  
Locally Advanced ◽  
Primary Objective ◽  
Clinical Activity ◽  
Correlative Analysis ◽  
Progression Of Disease ◽  
New Treatment ◽  
Grade 3 ◽  
Unacceptable Toxicity ◽  
Clinical Trial Information

192 Background: Chemotherapy in aPDAC has resulted in only modest improvements in outcome. The effectiveness of ICI monotherapy is also limited in PDAC, suggesting an immunogenic inert tumor microenvironment. SBRT is safe and effective in locally advanced PDAC and exhibits enhanced antitumor immunity. We hypothesize that ICI plus SBRT will improves immunomodulatory effects of ICI in patients with aPDAC resulting in a greater clinical benefit. Methods: Eligible patients with aPDAC were enrolled to four different treatment cohorts. Cohort 1: Durvalumab (Durva) 1500 mg every 4 weeks + SBRT 1 fraction x 8Gy on day 1. Cohort 2: SBRT 5 fractions x 5Gy followed by Durva. Cohort 3: Durva + Tremelimumab (Treme) 75 mg every 4 weeks + SBRT 1 fraction x 8Gy on day 1. Cohort 4: SBRT 5 fractions x 5Gy followed by Durva + Treme. This was continued until unacceptable toxicity or progression of disease. A biopsy was performed at baseline and pre-cycle 2 of treatment for exploratory correlative analysis. The primary objective was to evaluate the safety and feasibility of combining ICI and SBRT to enhance the efficacy of ICI. Results: 51 patients with aPDAC were enrolled and 31 patients were evaluable for the efficacy. The most commonly TRAEs were lymphopenia. Grade 3-4 AEs were lymphopenia and anemia. No dose limiting toxicities were seen. Out of total 31 evaluable patients, 1 patient achieved a confirmed partial response seen in Cohort 1 and 2 patients in Cohort 4, and 7 stable disease across the 4 treatment arms. Median PFS and OS was 1.7 months (95% CI 0.7-2.8 months) and 3.4 months (95% CI 0.9-11.4 months) in cohort 1; 2.6 months (95% CI 2.1-4.7 months) and 9.1 months (95% CI 3.4-18.7 months)in cohort 2; 1.6 months (95% CI 0.5-4.0 months) and 3.0 months (95% CI 0.7-6.6 months) in cohort 3; and 3.2 months (95% CI 1.5-16.5months) and 6.4 months (95% CI 1.5-17.6 months) in cohort 4. Conclusions: The combination of ICI and SBRT is safe and well tolerated in patients with aPDAC. The overall response rate of 9.6% including 2 patients who achieved a durable partial response lasting over 12 months, suggests meaningful clinical activity. This signifies that ICI and SBRT is a potential new treatment for aPDAC. Clinical trial information: NCT02311361.

scholarly journals Preliminary Results from a Phase 1 Study of HMPL-523, a Highly Selective Syk Inhibitor, in Chinese Patients with Mature B-Cell Lymphomas

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5324-5324 ◽  
Author(s):  
Jun Zhu ◽  
Junning Cao ◽  
Lugui Qiu ◽  
Junyuan Qi ◽  
Yuqin Song ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Phase 1 ◽  
Lung Infection ◽  
Chinese Patients ◽  
B Cell Lymphomas ◽  
Cancer Hospital ◽  
Syk Inhibitor ◽  
Grade 3 ◽  
Anti Tumor Activity

Abstract Background: Spleen tyrosine kinase (Syk) is a key component of B-cell receptor (BCR) signaling and is an established therapeutic target in multiple subtypes of B-cell lymphomas. HMPL-523 is an oral, selective Syk inhibitor, and has shown strong anti-tumor efficacy in xenograft models of B-cell malignancies. Here we report the safety, pharmacokinetics (PK) and preliminary anti-tumor activity results of the dose escalation stage in a Phase 1 study in patients with relapsed/refractory (R/R) B-cell lymphomas treated with HMPL-523 monotherapy (NCT02857998). Methods: This study comprised a dose escalation stage and a dose expansion stage. The primary objectives for the dose escalation stage were to evaluate the safety, tolerability, and to determine maximum tolerated dose (MTD) and /or recommended Phase 2 dose (RP2D) of HMPL-523. Secondary objectives were to assess the PK and preliminary anti-tumor activity. Treatment responses were assessed by the Lugano criteria, modified International Workshop on Chronic Lymphocytic Leukemia (CLL) guideline, or the consensus of international workshops on Waldenstrom Macroglobulinemia (WM), at weeks 8, 16, 24, and then every 12 weeks. Results: As of May 3rd 2018, 27 patients had been enrolled and dosed with one of the five dose levels of 200-800 mg once daily (QD) or 200 mg twice daily (BID) under the conventional "3+3" dose escalation design. Baseline tumor subtypes included follicular lymphoma (FL; n=10), diffuse large B cell lymphoma (DLBCL; n=5), CLL / small lymphocytic lymphoma (SLL; n=4), mantle cell lymphoma (MCL; n=4), marginal zone lymphoma (MZL; n=3) and WM (n=1). All patients (median age was 57 years [range 31-73]) were Asian, and 55.6% of the patients were male, with a median prior lines of therapy of 3 (range 1-6). All patients had received prior systemic chemotherapies and/or antibodies, including alkylating agents (100%), anti-CD20 antibodies (75%), and anthracyclines (95.8%). Three patients (8.3%) had received prior ibrutinib/placebo from clinical trials. Median follow-up time was 98 days (range, 8-427), and 70.4% of patients had discontinued therapy, mostly due to disease progression (25.9%) and adverse events (AEs) (14.8%). The AEs of any cause reported in more than 10% patients were leukopenia (44.4%), neutropenia (44.4%), alkaline phosphatase (ALT) increased (40.7%), aspartate aminotransferase (AST) increased (40.7%), thrombocytopenia (29.6%), blood bilirubin increased (29.6%), anaemia (25.9%), proteinuria (18.5%), amylases increased (18.5%), yellow skin (18.5%), hypokalaemia (14.8%), lung infection (14.8%), influenza syndrome (14.8%), hyperuricaemia (11.1%), cough (11.1%), and bilirubin conjugated increased (11.1%). The ≥ Grade 3 AEs of any cause reported in more than 5% patients were neutropenia (18.5%), lung infection (7.4%), and blood bilirubin increased (7.4%). Serious AEs were reported in 8 patients with 9 events, of which 5 events were considered to be related to HMPL-523 (i.e., interstitial pneumonia, febrile neutropenia, kidney failure, lung infection, and bilirubin conjugated increased). No fatal AE was reported. Five dose limiting toxicities (DLTs) were observed: 1 in the 200 mg QD cohort (Grade 3 amylase increased), 2 in the 800 mg QD cohort (Grade 3 febrile neutropenia; Grade 3 kidney failure), and 2 in the 200 mg BID cohort (Grade 3 bilirubin conjugated increased; Grade 4 hyperuricaemia and blood creatine phosphokinase increased). The MTD was reached at the 600 mg QD dose level which was determined as the RP2D. Preliminary PK data indicated that the exposures of HMPL-523 increased with the increase in dose from 200 mg QD to 800 mg QD. The geometric mean exposures indicated as AUCtau and Cmax at 600 mg QD at steady state were approximately 4,000 h•ng/mL and 300 ng/mL, respectively, and the t1/2 was in the range of 7-15 hours across all dose levels. Among 21 efficacy evaluable patients with at least one post treatment efficacy assessment, best tumor response was seen in 4 (19.0%) patients who achieved partial response (3/10 FL, and 1/3 CLL/SLL), and 9 (40%) patients who achieved stable disease (3/4 MCL, 3/10 FL, 1/3 CLL/SLL, 1/2 MZL, and 1/1 WM). Conclusions: HMPL-523 is well tolerated as a single agent in Chinese patients with R/R B-cell lymphomas. MTD was reached and RP2D was determined to be 600 mg QD. Preliminary anti-tumor activity was observed in indolent lymphomas, including CLL/SLL and FL. Disclosures Zhu: Beijing Cancer Hospital: Employment. Song:Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Hua:Hutchison Medipharma: Employment. Yang:Hutchison Medipharma: Employment. Yu:Hutchison Medipharma: Employment. Wang:Hutchison Medipharma: Employment. Dai:Hutchison Medipharma: Employment. Su:Hutchison Medipharma: Employment.

Relationship of bone marrow blast (BMBL) response to overall survival (OS) in a multicenter study of rigosertib (Rigo) in patients (pts) with myelodysplastic syndrome (MDS) with excess blasts progressing on or after treatment with a hypomethylating agent (HMA).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7056-7056
Author(s):  
Aref Al-Kali ◽  
Devendra Hiwase ◽  
Maria R. Baer ◽  
Peter Greenberg ◽  
Jake Shortt ◽  
...  
Keyword(s):  
Phase 1 ◽  
Early Death ◽  
Complete Response ◽  
International Prognostic Scoring System ◽  
Kaplan Meier ◽  
Grade 3 ◽  
Relationship Of ◽  
Very High ◽  
Unacceptable Toxicity ◽  
Clinical Trial Information

7056 Background: No therapies are approved for MDS after HMA failure. 04-24 was a single-arm study to evaluate best BMBL response as a potential surrogate for OS in higher-risk (HR) MDS pts who progressed on or after an HMA. Rigo is a Ras-mimetic that inhibits the RAS-RAF-MEK pathway, which is frequently activated in HR MDS (Athuluri-Divakar Cell 2016; Gil-Bazo Cancer Biol Ther 2016). Methods: Eligible MDS pts had 5-30% BMBL confirmed within 6 wks pre-study and progression per International Working Group (IWG) 2006 criteria on or after HMAs within 2 yrs. Rigo 1800 mg/24 hrs was continuously infused over 72 hrs q 2 wks × 8 cycles, then q 4 wks until progression or unacceptable toxicity. Primary endpoint was relationship of best BMBL IWG response to OS by Kaplan Meier method. Results: 64 pts were treated (median 5 cycles, range 1-32+), with 61% male, median age 73 (range 47-87), median prior HMA duration 10.8 mos (range 1.2-70.2). Revised International Prognostic Scoring System scores were low 2%, intermediate 11%, high 27%, very high 53%, and unknown 8%. ≥Grade 3 adverse events in ≥10% of pts were anemia 19%, thrombocytopenia 19%, and febrile neutropenia 16%. At the analysis time 40 pts (63%) had died. Best BMBL IWG response was marrow complete response (mCR) 14 pts (22%), stable disease (SD) 30 (47%), progressive disease (PD) 15 (23%), and failure (early death/withdrawal) 5 (8%); 2 mCR pts had transplant. Median OS was 7.0 mos (95% confidence interval 4.8-10.8). Landmark median OS (from day of best BMBL response) was mCR not reached; SD 6.3 mos; PD 3.3 mos. Median OS of mCR+SD was 8.5 mos, with log-rank p = 0.011 (mCR+SD OS to PD OS). Conclusions: BMBL response is a predictor of survival for MDS pts receiving Rigo after HMA failure, confirming findings in earlier Phase 1/2 studies (Silverman ASCO 2015 Abstr 7017). Based on earlier results identifying an MDS subset benefitting from Rigo (Garcia-Manero Lancet Oncol 2016; ASCO 2016 Abstr 165681), a randomized Phase 3 trial of Rigo vs physician’s choice (INSPIRE) is ongoing to determine if Rigo improves survival after HMA failure within 9 cycles. Clinical trial information: NCTO 1928537.

Venetoclax (VEN) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e19041-e19041
Author(s):  
Matthew Steven Davids ◽  
Andrew Warwick Roberts ◽  
John Francis Seymour ◽  
William G. Wierda ◽  
Soham D. Puvvada ◽  
...  
Keyword(s):  
Phase 1 ◽  
Cell Transplant ◽  
Significant Activity ◽  
Non Hodgkin Lymphoma ◽  
Mantle Cell ◽  
Orally Bioavailable ◽  
Grade 3 ◽  
Unacceptable Toxicity ◽  
Clinical Trial Information

e19041 Background: VEN is a selective orally bioavailable BCL-2 inhibitor. The dose-escalation Phase 1 study of VEN in 106 patients (pts) with relapsed/refractory NHL reported an ORR of 44%. Most pts had diffuse large B-cell/follicular lymphoma; we report on updated results in pts with less common NHL subtypes. Methods: VEN was administered and continued until progressive disease (PD)/unacceptable toxicity, in dose cohorts ranging from 300–1200 mg. Adverse events (AEs) were assessed by NCI-CTCAE v4.0 and response by 2007 Cheson IWG response criteria, utilizing CT scans beginning at wk 6. Results: 35 of 106 pts had mantle cell lymphoma (MCL, n=28), marginal zone lymphoma (MZL, n=3) or Waldenström macroglobulinemia (WM, n=4). Most common all grade treatment emergent AEs were nausea (51%), diarrhea (49%) and fatigue (34%); grade 3/4 AEs in >10% of pts were neutropenia and anemia (17% each). Laboratory TLS was reported in a single pt (bulky MCL). MCL pts (median age: 72 years) had received a median of 3 (1–7) prior treatments (tx). Median time from start of prior tx to start of VEN was 13 mo (2–148) and time on VEN was 11 mo (0.2–42). ORR was 75%, 6 pts (21%) achieved CR and remain on study (DORs: 25–40 mo). One pt with a PR proceeded to elective allogeneic stem cell transplant and remained disease free at last protocol defined follow-up (24 mo after coming off study). Median PFS was 11 mo and DOR was 15 mo. MZL pts (median age: 63 years) had received a median of 4 (2–6) prior tx. Time from start of prior tx to start of VEN was 8, 14, 73 mo and time on VEN was 5, 1, 35 mo. One pt (6 prior tx) received VEN for <1 mo due to progressive cytopenias; 1 pt (4 prior tx) achieved a PR with VEN at wk 6 but had PD at wk 16; 1 pt (2 prior tx) achieved PR at wk 6 and is the only pt to remain on study (DOR:32 mo). WM pts (median age: 67 years) had a median of 4 (3–5) prior tx. Time from start of prior tx to start of VEN was 5, 18, 33, 67 mo and time on VEN was 42, 17, 54, 20 mo. All pts achieved PR (at wks 6 [n=2], 16 and 36), with DORs of 11, 12, 38 and 50+ mo (latter is ongoing and remains on study). Conclusions: VEN monotherapy has a tolerable safety profile in MCL, MZL and WM pts. ORR were high and most responses durable; median PFS and DOR suggest significant activity in MCL pts. Further investigation of VEN in each disease is indicated. Clinical trial information: NCT01328626.

406 CDX527–01, a phase 1 dose-escalation and expansion study of the PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A431-A431
Author(s):  
Michael Yellin ◽  
Tracey Rawls ◽  
Diane Young ◽  
Philip Golden ◽  
Laura Vitale ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Clinical Studies ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Clinical Activity ◽  
Tumor Types ◽  
Anti Tumor Activity

BackgroundCD27 ligation and PD-1 blockade elicit complementary signals mediating T cell activation and effector function. CD27 is constitutively expressed on most mature T cells and the interaction with its ligand, CD70, plays key roles in T cell costimulation leading to activation, proliferation, enhanced survival, maturation of effector capacity, and memory. The PD-1/PD-L1 pathway plays key roles in inhibiting T cell responses. Pre-clinical studies demonstrate synergy in T cell activation and anti-tumor activity when combining a CD27 agonist antibody with PD-(L)1 blockade, and clinical studies have confirmed the feasibility of this combination by demonstrating safety and biological and clinical activity. CDX-527 is a novel human bispecific antibody containing a neutralizing, high affinity IgG1k PD-L1 mAb (9H9) and the single chain Fv fragment (scFv) of an agonist anti-CD27 mAb (2B3) genetically attached to the C-terminus of each heavy chain, thereby making CDX-527 bivalent for each target. Pre-clinical studies have demonstrated enhanced T cell activation by CDX-527 and anti-tumor activity of a surrogate bispecific compared to individual mAb combinations, and together with the IND-enabling studies support the advancement of CDX-527 into the clinic.MethodsA Phase 1 first-in-human, open-label, non-randomized, multi-center, dose-escalation and expansion study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of CDX-527 is ongoing. Eligible patients have advanced solid tumor malignancies and have progressed on standard-of-care therapy. Patients must have no more than one prior anti-PD-1/L1 for tumor types which have anti-PD-1/L1 approved for that indication and no prior anti-PD-1/L1 for tumor types that do not have anti-PD-1/L1 approved for that indication. CDX-527 is administered intravenously once every two weeks with doses ranging from 0.03 mg/kg up to 10.0 mg/kg or until the maximum tolerated dose. The dose-escalation phase initiates with a single patient enrolled in cohort 1. In the absence of a dose limiting toxicity or any ≥ grade 2 treatment related AE, cohort 2 will enroll in a similar manner as cohort 1. Subsequent dose-escalation cohorts will be conducted in 3+3 manner. In the tumor-specific expansion phase, up to 4 individual expansion cohort(s) of patients with specific solid tumors of interest may be enrolled to further characterize the safety, PK, PD, and efficacy of CDX 527. Tumor assessments will be performed every 8-weeks by the investigator in accordance with iRECIST. Biomarker assessments will include characterizing the effects on peripheral blood immune cells and cytokines, and for the expansion cohorts, the impact of CDX-527 on the tumor microenvironment.ResultsN/AConclusionsN/ATrial RegistrationNCT04440943Ethics ApprovalThe study was approved by WIRB for Northside Hospital, approval number 20201542

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