Talabostat and Pembrolizumab for the Treatment of Advanced Solid Cancers

A Phase 2 Basket Study of BXCL701, a Small Molecule Inhibitor of Dipeptidyl Peptidases (DPP), Administered in Combination With Pembrolizumab in Patients With Advanced Solid Cancers

This phase II trial studies the side effects of talabostat and pembrolizumab and to see how well they work for the treatment of solid cancers that have spread to other places in the body (advanced). Talabostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving talabostat and pembrolizumab may help control the disease.

Study Overview

• Status: Terminated
• Conditions: Advanced Malignant Solid Neoplasm; Recurrent Malignant Solid Neoplasm
• Intervention / Treatment: Biological: Pembrolizumab; Drug: Talabostat Mesylate

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate response rate per Response Evaluation Criteria in Solid Tumors (RECIST) and immune (i)RECIST in patients treated in cohort A and in patients treated in cohort B.

II. To evaluate dose-limiting toxicities (DLT) in the first 6 patients enrolled to the study.

SECONDARY OBJECTIVES:

I. To evaluate progression-free survival (PFS). II. To evaluate duration of response (DOR). III. To evaluate overall survival (OS). IV. To evaluate overall safety and tolerability.

EXPLORATORY OBJECTIVES:

I. To evaluate the quantitative and qualitative effects of talabostat (BXCL701) in combination with pembrolizumab on relevant immune effector cytokines in blood.

II. To evaluate the quantitative and qualitative effects of BXCL701 in combination with pembrolizumab on various immunological effector cells, including neutrophils, myeloid derived suppressor cells (MDSCs), dendritic cells, cancer associated fibroblast (CAF), T-cells and macrophage density in pre-dose tumor biopsies and when feasible in post-dose tumor tissues.

III. To explore the predictive value of baseline programmed death ligand 1 (PD-L1) tumor expression and tumor mutation burden (TMB) with clinical outcomes.

IV. To evaluate changes in serially collected blood circulating tumor deoxyribonucleic acid (DNA) (ctDNA) to assess for tumor response and clonal evolution.

V. To evaluate pre- and post-treatment PD-L1 positron emission tomography (PET)/computed tomography (CT) as a predictive tool for therapeutic efficacy.

OUTLINE:

Patients receive talabostat orally (PO) twice daily (BID) on days 1-14 and pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient with a histology or cytology proven solid advanced cancer, which failed or is intolerant of standard therapies known to offer survival benefit unless standard therapies include PD1 or PD-L1 antibodies

  • Lead-in stage: patient with advanced cancers meeting the criteria above with or without prior treatment with PD1/PDL1 antibodies. Patients with prior treatment with PD1/PDL1 antibodies should be relapsed
  • Efficacy stage cohort A: patients with advanced cancers not previously treated with PD1/PDL1 antibodies
  • Efficacy stage cohort B: patients with advanced cancers which have relapsed or progressed with PD1/PDL1 antibodies
• Patient with a life expectancy of more than 3 months, in the opinion of the investigator
• Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0 2
• Patients < 18 years of age have to weigh > 40 kgs
• Patients must have measurable disease by RECIST 1.1 and iRECIST. Disease amenable to a biopsy is not mandatory
• Patient's acute toxic effects of previous anticancer therapy have resolved to =< grade 1 except for grade 2 peripheral neuropathy or any grade of alopecia
• Serum creatinine =< 1.5 times institutional upper limit of normal (ULN) or calculated creatinine clearance > 40 mL/min
• Serum albumin >= 2.5 g/dL
• Total bilirubin =< 1.5 x ULN (for patients with known Gilbert syndrome < 3 x ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x institutional ULN (patients with hepatic metastases must have AST/ALT =< 5 x ULN)
• Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
• Hemoglobin >= 8 g/dL and no red blood cell transfusions during the prior 7 days
• Platelet count >= 75 x 10^9/L
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 14 days prior to the initiation of treatment and/or postmenopausal women must be amenorrhoeic for at least 12 months to be considered of non-childbearing potential. Women of childbearing potential must agree and commit to the use of 2 highly effective methods of birth control throughout the duration of the study until at least 4 months following the last dose of study drug. Acceptable methods are defined as those that result, alone or in combination, in a low failure rate (ie, less than 1% per year) when used consistently and correctly, such as surgical sterilization, an intrauterine device, or hormonal contraception in combination with a barrier method. It is currently unknown whether BXCL701 or pembrolizumab may reduce the effectiveness of systemically acting hormonal contraceptives; therefore, women using systemically acting hormonal contraceptives should add a barrier method. In certain countries (if permitted by law), WOCBP may agree to abide by heterosexual sexual abstinence during the time of participation in this study
• Male patients and their female partners of childbearing potential must agree and commit to use a barrier contraception (eg, condom with spermicidal foam/gel/film/cream/suppository) throughout the duration of the study until at least 60 days following the last dose of study drug, in addition to their female partners using either an intrauterine device or hormonal contraception and continuing until at least 4 months days following the last dose of study drug. This criterion may be waived for male patients who have had a vasectomy > 6 months before signing the informed consent form (ICF)
• Patient has signed informed consent prior to initiation of any study-specific procedures or treatment
• Patient is able to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

• Patient cannot swallow oral medication
• Patient is on gliptins
• Patient has active central nervous system (CNS) metastases not controlled by prior surgery or radiotherapy (patient must be off steroids). Patients with signs or symptoms suggestive of brain metastasis are not eligible unless brain metastases are ruled out by brain magnetic resonance imaging/computed tomography (MRI/CT)
• Patient has received external-beam radiation or another systemic anticancer therapy within 14 days or 5 half-lives, whichever is shorter, prior to study treatment
• Patient has received treatment with an investigational systemic anticancer agent within 14 days prior to study drug administration
• Patient has an additional active malignancy that may confound the assessment of the study endpoints. Patients with the following concomitant neoplastic diagnoses are eligible: non-melanoma skin cancer and carcinoma in situ (including transitional cell carcinoma, anal carcinoma, and melanoma in situ). Patients with simultaneous cancers, which are not active and do not require treatment may be eligible contingent on discussion with the principle investigator (PI) and supporter
• Patient has clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication)
• Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a prednisone equivalent dose of > 10 mg daily for at least 1 week or other form of immunosuppressive therapy within 7 days prior to cycle 1 day 1 (C1D1)
• Patient has uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness/social situations that would limit compliance with study requirements
• Patient has known positive status for human immunodeficiency virus active or chronic hepatitis B or hepatitis C. Patients with history of hepatitis B or C and undetectable viral load are eligible. Screening is not required
• Has a clinically significant upper gastrointestinal obstruction, abnormal physiological function or malabsorption syndrome that may affect the absorption of the study medication
• Patient has any medical condition which, in the opinion of the investigator, places the patient at an unacceptably high risk for toxicity
• Patient is pregnant or breast-feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (talabostat, pembrolizumab); Patients receive talabostat PO BID on days 1-14 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Biological: Pembrolizumab; Given IV; Other Names: Keytruda; MK-3475; Lambrolizumab; SCH 900475; Drug: Talabostat Mesylate; Given PO; Other Names: Val-boro-Pro

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Control Rate Per RECIST v1.1	Disease control rate was defined as the percentage of patients who had complete response (CR), partial response (PR), or stable disease (SD) according to RECIST v1.1.	At baseline and at the end of Cycle 3 (approximately 9 weeks after the first study treatment dose), and then approximately every 9 weeks thereafter until development of progressive disease, up to 3 years
Immune-related Disease Control Rate Per iRECIST	Immune-related disease control rate was defined as the percentage of patients who had immune-related complete response (iCR), immune-related partial response (iPR), or immune-related stable disease (iSD) according to iRECIST.	At baseline and at the end of Cycle 3 (approximately 9 weeks after the first study treatment dose), and then approximately every 9 weeks thereafter until development of progressive disease, up to 3 years
Dose-limiting Toxicities (DLTs)	A DLT was defined as any of the following AEs occurring during Cycle 1, regardless of investigator attribution to study treatment: Any Grade 4 laboratory abnormality, regardless of duration.; Any Grade 3 laboratory abnormalities if associated with clinical symptoms regardless of duration; Any Grade ≥3 non-hematologic AE, with the exceptions of Grade ≥3 nausea, vomiting, diarrhea, constipation, and fatigue, that resolves to Grade ≤1 within 72 hours with optimal medical management and/or supportive measures.; Grade ≥3 thrombocytopenia with Grade >1 bleeding or requirement for platelet transfusion.; Grade ≥3 febrile neutropenia.; Grade ≥3 fever.; Grade ≥3 skin rash.; AST or ALT >3 × upper limit of normal [ULN] with concomitant total bilirubin >2 × ULN.; Any toxicity resulting in ≥30% held/skipped doses of BXCL701 during Cycle 1.; Delay of Cycle 2 by ≥14 days due to toxicity.; Any other significant toxicity considered by the investigatoro be dose-limiting.	DLT was assessed during Cycle 1 (21-day cycle)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS) by RECIST v1.1	PFS was defined as the time from administration of the first dose to the first documented disease progression by RECIST v1.1 or death due to any cause, whichever occurs first. Patients who were alive and had not experienced disease progression at the time of data cutoff were censored.	At baseline and at the end of Cycle 3 (approximately 9 weeks after the first study treatment dose), and then approximately every 9 weeks thereafter until development of progressive disease, up to 3 years
Progression-free Survival (PFS) by iRECIST	PFS was defined as the time from administration of the first dose to the first documented disease progression by iRECIST v1.1 or death due to any cause, whichever occurs first. Patients who were alive and had not experienced disease progression at the time of data cutoff were censored.	At baseline and at the end of Cycle 3 (approximately 9 weeks after the first study treatment dose), and then approximately every 9 weeks thereafter until development of progressive disease, up to 3 years
Overall Survival (OS)	Overall survival was measured from the first date of administration of the study drug to the date of death due to any cause. Patients who were alive at the last follow-up examination were censored.	From the first date of administration of the study drug to the date of data cut-off (January 7, 2024)
Treatment-related Adverse Event (TRAE)	All safety data from all patients, who received at least one dose of study drug were included in safety analysis. Each AE (as defined by NCI CTCAE v5) was counted only once for a given subject. In the event a patient experienced repeated episodes of the same AE, then the event with the highest severity and/or strongest causal relationship to study treatment was used for purposes of tabulations.	Patients were monitored for AE from the first day of administration of study medication through 30 days following the last dose of BXCL701 and or pembrolizumab, an average of 3 years.

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Aung Naing, MD, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): March 19, 2020
• Primary Completion (Actual): March 11, 2025
• Study Completion (Actual): March 11, 2025

Study Registration Dates

• First Submitted: November 18, 2019
• First Submitted That Met QC Criteria: November 19, 2019
• First Posted (Actual): November 20, 2019

Study Record Updates

• Last Update Posted (Actual): May 16, 2025
• Last Update Submitted That Met QC Criteria: May 6, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Pembrolizumab
• Other Study ID Numbers: 2019-0748 (Other Identifier: M D Anderson Cancer Center); NCI-2019-07569 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No