Phase II trial of the CDK4/6 inhibitor abemaciclib in patients (pts) with advanced and refractory well‐differentiated gastroenteropancreatic neuroendocrine tumors (GEP NETs).

TPS376 Background: Despite advances in the treatment of advanced GEP NETs, long‐term disease control remains a challenge. Overexpression and altered regulation of cyclin-dependent kinases (CDK) 4 and 6 have been observed in multiple subtypes of GEP NETs. Preclinical studies have demonstrated that the CDK 4/6 inhibitor palbociclib reduces growth of pancreatic NET cell lines and levels of phosphorylated retinoblastoma protein in vitro. Moreover, the drug significantly inhibited tumor growth in vivo in pancreatic NET xenograft models. Abemaciclib is a selective small molecule CDK 4/6 inhibitor, approved for the treatment of HR+ HER2– metastatic breast cancer. Clinical activity and central nervous system penetration of the drug have been observed in several tumor types in clinical trials, including partial response in one pt with metastatic small intestinal NET. We have developed a Phase 2 trial of abemaciclib in GEP NETs to evaluate its efficacy and safety in these rare cancers. Methods: This is an investigator-initiated non-randomized phase 2 trial using a two-stage design. Eligible pts have metastatic or locally advanced unresectable well-differentiated grade 1-2 GEP NETs, ECOG PS 0-2, and must have progressed on at least one line of systemic therapy. Prior or concurrent treatment with somatostatin analogs is allowed,. Abemaciclib is administered at a dose of 200 mg orally every 12 hours continuously in 28-day cycles. Dose reductions for toxicities are allowed to level -1 (150 mg) and -2 (100 mg). Primary endpoint is objective response rate (ORR) by RECIST v1.1. Secondary endpoints include progression free survival (PFS), overall survival (OS), and toxicity. A two‐stage design with 88% power to detect an increase in ORR to 20% with abemaciclib at the 1‐sided 0.05 level would require a total of 37 patients. Stage 1 will include 20 patients, and if one response is seen among these patients, the study will continue to enroll another 17 patients. The trial was activated in January 2020, and 3 patients have been enrolled to date. Available archival tumor tissue and molecular profiling data are collected for future correlative studies including assessment of response biomarkers.

Download Full-text

An adaptive Simon Two-Stage Design for Phase 2 studies of targeted therapies

Contemporary Clinical Trials ◽

10.1016/j.cct.2007.02.008 ◽

2007 ◽

Vol 28 (5) ◽

pp. 654-661 ◽

Cited By ~ 44

Author(s):

Cheryl L. Jones ◽

Eric Holmgren

Keyword(s):

Targeted Therapies ◽

Phase 2 ◽

Two Stage ◽

Stage Design ◽

Two Stage Design

Download Full-text

TROPHY-u-01: A phase II open-label study of sacituzumab govitecan (IMMU-132) in patients with advanced urothelial cancer after progression on platinum-based chemotherapy and/or anti-PD-1/PD-L1 checkpoint inhibitor therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.tps495 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. TPS495-TPS495 ◽

Cited By ~ 1

Author(s):

Scott T. Tagawa ◽

Daniel Peter Petrylak ◽

Petros Grivas ◽

Neeraj Agarwal ◽

Cora N. Sternberg ◽

...

Keyword(s):

Urothelial Cancer ◽

Checkpoint Inhibitor ◽

Objective Response ◽

Locally Advanced ◽

Low Grade ◽

Phase 2 ◽

Open Label ◽

Phase 2 Trial ◽

Metastatic Urothelial Cancer ◽

Platinum Based Chemotherapy

TPS495 Background: Patients (pts) with unresectable locally advanced or metastatic urothelial cancer (mUC) who progress after platinum-based chemotherapy and checkpoint inhibitor (CPI) therapy and pts ineligible for platinum-based chemotherapy who progress after CPI have limited treatment options and poor outcomes. Trop-2 is an epithelial cell surface antigen that is overexpressed in UC. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate that targets Trop-2 and delivers the active metabolite (SN38) of the topoisomerase I inhibitor irinotecan to tumor cells. In a phase 1/2 single-arm trial, pts with advanced cancers received SG 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle; preliminary results in the cohort of 41 evaluable pts with mUC and a median of 3 (range 1–6) prior therapies showed an objective response rate (ORR) of 34%. Adverse events (AE) were mostly low grade, including diarrhea (63%), nausea (56%), and fatigue (49%). Neutropenia (all grades) occurred in 49% of pts (≥ grade 3/4, 39%; treatment-related serious AE of febrile neutropenia, 5%). Median overall survival was 16.1 months, and median progression-free survival was 7.1 months. These results warrant further investigation in a dedicated phase 2 trial. Methods: TROPHY-U-01 is a single-arm, open-label, global phase 2 trial evaluating the antitumor activity and safety of SG in 140 pts with advanced UC. The primary cohort (progression after platinum chemotherapy and CPI) will enroll 100 pts in a Simon 2-stage design with > 90% power accounting for dropouts to exclude the null hypothesis or ORR < 12%, while a second cohort (40 pts) will comprise cisplatin-ineligible pts who received prior CPI. The primary objective is ORR per RECIST 1.1, assessed by central review. Secondary objectives include response duration, PFS, OS, and safety/tolerability. Enrollment began in August 2018. Clinical trial information: NCT03547973.

Download Full-text

Durvalumab and pazopanib in patients with advanced soft tissue sarcoma: A single-center, single-arm, phase 2 trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.11551 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 11551-11551

Author(s):

Hyo Song Kim ◽

Hee Jin Cho ◽

Kum-Hee Yun ◽

Young Han Lee ◽

Sung Hyun Kim ◽

...

Keyword(s):

Soft Tissue ◽

Soft Tissue Sarcoma ◽

Objective Response ◽

Locally Advanced ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Phase 2 ◽

Single Center ◽

Phase 2 Trial ◽

Ecog Ps

11551 Background: Based on the central role played by the vascular endothelial growth factor receptor (VEGFR) in immunosuppression, we assessed the activity and safety of VEGFR inhibitor pazopanib plus anti-PD-L1 blockade durvalumab in soft tissue sarcoma (STS). Methods: We did a single-arm, single-center, phase 2 study that enrolled patients with metastatic or locally advanced STS aged 19 years or older, ECOG PS 0-1, with at least one measurable lesion, and received at least one previous line of systemic therapy. Patient were given pazopanib 800 mg orally daily and durvalumab 1500 mg intravenously for 60 min every 3 weeks. The primary endpoint was investigator-assessed objective response. Results: Between September 2019 and October 2020, 47 participants were enrolled, of whom 46 (97.9%) were evaluable for the efficacy analyses. With a median follow up of 12.3 months, complete and partial response (PR) was achieved in 1 (2.2%) and 12 (26.1%) patients, resulting in 28.3 % of objective response rate. Median time to achieve PR was 1.4 months and median duration of response was 11.0 months. The most common treatment-related adverse events of any grade include fatigue (20 [42.6%]), anorexia (17 [36.2%]), diarrhea (17 [36.2%]), and AST elevation (16, [34.0%]). Thirty-one patients (67.3%) had progressive disease, and the median progression free survival was 8.6 months (95% CI 3.6-13.6). Conclusions: Durvalumab and pazopanib showed encouraging activity in patients with advanced STS. Molecular predictors with whole exome and RNA sequencing will be presented. Clinical trial information: NCT03798106.

Download Full-text

JAVELIN BRCA/ATM: A phase 2 trial of avelumab (anti–PD-L1) plus talazoparib (PARP inhibitor) in patients with advanced solid tumors with a BRCA1/2 or ATM defect.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.tps2660 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. TPS2660-TPS2660 ◽

Cited By ~ 1

Author(s):

David Michael Hyman ◽

Amelia B. Zelnak ◽

Todd Michael Bauer ◽

Susanna Varkey Ulahannan ◽

James M. Ford ◽

...

Keyword(s):

Prostate Cancer ◽

Immune Checkpoint ◽

Parp Inhibitor ◽

Objective Response ◽

Locally Advanced ◽

The United States ◽

Prior Treatment ◽

Pharmacokinetic Parameters ◽

Phase 2 ◽

Phase 2 Trial

TPS2660 Background: Defects in DNA damage response genes, including BRCA1/2 and ATM, confer sensitivity to PARP inhibitors. Talazoparib is a potent, oral PARP inhibitor with a dual mechanism of action (PARP enzyme inhibition and PARP trapping). Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody with a wild-type Fc region that has shown clinical activity in multiple tumor types. Preclinical and early clinical data suggest that combining a PARP inhibitor with an immune checkpoint inhibitor may provide improved activity. Methods: JAVELIN BRCA/ATM (NCT03565991) is an ongoing, open-label, multicenter, phase 2 trial assessing the combination of avelumab and talazoparib. Enrollment of ≈200 patients with a histologically confirmed locally advanced or metastatic solid tumor that has progressed on > 1 line of standard-of-care treatment for locally advanced or metastatic disease and has a germline or somatic defect in BRCA1 or 2 (cohort 1) or ATM (cohort 2) genes is planned. Patients with concomitant defects in > 1 gene ( BRCA1, BRCA2, or ATM) will be enrolled in cohort 1. Exclusion criteria include prior treatment with an immune checkpoint or PARP inhibitor, prior treatment with any other anticancer or radiation therapy within 2 weeks prior to enrollment, a known history of an immune-mediated or autoimmune condition, and known symptomatic brain metastases requiring steroids. The primary endpoint is confirmed objective response by blinded independent central review according to RECIST v1.1 and according to the Prostate Cancer Working Group 3 (PCWG3) for patients with metastatic castration-resistant prostate cancer (mCRPC). Secondary endpoints include safety; investigator-assessed confirmed objective response, time to tumor response, duration of response, and progression-free survival (per RECIST v1.1 and per PCWG3 for patients with mCRPC); overall survival; pharmacokinetic parameters; and potential predictive biomarkers. The study is currently enrolling patients at centers in the United States and Europe. Clinical trial information: NCT03565991.

Download Full-text

428 Interim analysis of Phase 2 results for cemiplimab in patients with metastatic basal cell carcinoma (mBCC) who progressed on or are intolerant to hedgehog inhibitors (HHIs)

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0428 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A453-A453

Author(s):

Karl Lewis ◽

Ketty Peris ◽

Aleksandar Sekulic ◽

Alexander Stratigos ◽

Lara Dunn ◽

...

Keyword(s):

Cell Carcinoma ◽

Interim Analysis ◽

Objective Response ◽

Locally Advanced ◽

Progression Free Survival ◽

Good Clinical Practice ◽

Phase 2 ◽

Curative Surgery ◽

Pivotal Phase ◽

Study Protocols

BackgroundHHIs, vismodegib and sonidegib, are approved for treatment of patients with mBCC or locally advanced BCC who are not candidates for surgery or radiation. There is no approved option for patients who progress on or are intolerant to HHIs. Cemiplimab is an anti-programmed cell death-1 monoclonal antibody approved for treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. Here we present the prespecified interim analysis of the mBCC cohort from the pivotal Phase 2, non-randomized, multi-center study of cemiplimab in patients with advanced BCC who discontinued HHI therapy due to disease progression, intolerance, or no better than stable disease after 9 months (NCT03132636).MethodsPatients with mBCC (nodal and/or distant) received cemiplimab 350 mg intravenously every 3 weeks; interim analysis included patients with the opportunity to be followed for approximately 57 weeks. The primary endpoint was objective response rate (ORR) per independent central review (ICR). Secondary objectives included assessment of safety and tolerability, estimation of duration of response (DOR), progression-free survival (PFS), and overall survival (OS).ResultsIn this interim efficacy analysis of 28 patients, 82.1% were males and median age was 65.5 years (range 38−90). Six patients had a partial response, per ICR, for an ORR of 21.4% (95% CI, 8.3, 41.0). ORR per investigator assessment was 28.6% (95% CI, 13.2, 48.7). Among responders, observed DOR was 9−23 months. Median time to response per ICR was 3.2 months (range, 2.1−10.5). Median Kaplan–Meier (KM) estimation of PFS was 8.3 months. Median DOR had not been reached and median KM estimation of OS was 25.7 months. All six responses had observed durations of at least 8 months. The disease control rate was 67.9% (95% CI, 47.6, 84.1).The most common treatment emergent adverse events (TEAEs) regardless of attribution were fatigue (50.0%), diarrhea (35.7%), pruritus (25.0%), and constipation (25.0%). Hypertension (n=2) was the only Grade ≥3 TEAE regardless of attribution occurring in ≥2 patients. TEAEs leading to death occurred in one (3.6%) patient who died from staphylococcal pneumonia, considered unrelated to study treatment.ConclusionsThis interim analysis demonstrates that cemiplimab is the first agent to provide clinically meaningful anti-tumor activity, including durable responses, in patients with mBCC after progression or intolerance on HHI therapy.AcknowledgementsEditorial acknowledgment: Medical writing support was provided by Cindi Hoover, PhD of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc. and Sanofi.Ethics ApprovalThe study protocols and all amendments were approved by the institutional review board at each participating study site. The study was conducted in accordance with the principles of the Declaration of Helsinki and with Good Clinical Practice guidelines as defined by the International Conference on Harmonization. All patients provided written informed consent before enrollment.

Download Full-text