Advanced Malignant Solid Neoplasm, Recurrent Malignant Solid Neoplasm
Conditions
Brief summary
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.
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.
Interventions
BIOLOGICALPembrolizumab
Given IV
Given PO
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate Per 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 | 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. |
| Immune-related Disease Control Rate Per 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 | 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. |
| Dose-limiting Toxicities (DLTs) | DLT was assessed during Cycle 1 (21-day cycle) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) by 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 | 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. |
| Treatment-related Adverse Event (TRAE) | 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. | 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. |
| Progression-free Survival (PFS) by 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 | 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. |
| Overall Survival (OS) | From the first date of administration of the study drug to the date of data cut-off (January 7, 2024) | 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. |
Countries
United States
Participant flow
Recruitment details
This is an open-label, single-institution, Phase 2 study of BXCL701 administered orally and daily, combined with pembrolizumab, in PD1/PDL1 or CTLA-4 naïve and PD1/PDL1 or CTLA-4 pretreated patients with advanced solid cancers at The University of Texas MD Anderson Cancer Center.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: PD-1/PD-L1 and/or CTLA-4 Inhibitor Treatment naïve BXCL701: 0.3 mg orally twice a day on Days 1 to 14 of a 21-day cycle plus pembrolizumab 200 mg administered IV on Day 1 every 21 days | 14 |
| Cohort B: PD-1/PD-L1 and/or CTLA-4 Inhibitor Pretreated BXCL701: 0.3 mg orally twice a day on Days 1 to 14 of a 21-day cycle plus pembrolizumab 200 mg administered IV on Day 1 every 21 days | 17 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Clinical PD and extended treatment holding/ Patient choice/withdrew consent | 1 | 1 |
| Overall Study | Clinical PD/Patient choice | 1 | 0 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lack of Efficacy | 9 | 13 |
| Overall Study | Toxicity/ Patient choice | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Total | Cohort A: PD-1/PD-L1 and/or CTLA-4 Inhibitor Treatment naïve | Cohort B: PD-1/PD-L1 and/or CTLA-4 Inhibitor Pretreated |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 11 Participants | 7 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 7 Participants | 13 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 21 Participants | 9 Participants | 12 Participants |
| Region of Enrollment United States | 31 participants | 14 participants | 17 participants |
| Sex: Female, Male Female | 14 Participants | 6 Participants | 8 Participants |
| Sex: Female, Male Male | 17 Participants | 8 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 26 / 31 |
| other Total, other adverse events | 29 / 31 |
| serious Total, serious adverse events | 17 / 31 |
Outcome results
Primary
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.
Time frame: 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
Population: To be evaluable for response, patients must have completed at least 9 weeks of treatment and received at least 70% of the total planned talabostat dose in cycles 1 and 2.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: PD-1/PD-L1 and/or CTLA-4 Inhibitor Treatment naïve | Disease Control Rate Per RECIST v1.1 | 4 Participants |
| Cohort B: PD-1/PD-L1 and/or CTLA-4 Inhibitor Pretreated | Disease Control Rate Per RECIST v1.1 | 4 Participants |
Primary
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.
Time frame: DLT was assessed during Cycle 1 (21-day cycle)
Population: DLT was assessed in the first 6 patients enrolled on the study. Unless doses were held because of DLT, a patient must have received \>70% of their BXCL701 in Cycle 1 (i.e., ≥30 of 42 planned doses) with pembrolizumab dosed on Day 1 of Cycle 1
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: PD-1/PD-L1 and/or CTLA-4 Inhibitor Treatment naïve | Dose-limiting Toxicities (DLTs) | 1 Participants |
| Cohort B: PD-1/PD-L1 and/or CTLA-4 Inhibitor Pretreated | Dose-limiting Toxicities (DLTs) | 0 Participants |
Primary
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.
Time frame: 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
Population: To be evaluable for response, patients must have completed at least 9 weeks of treatment and received at least 70% of the total planned talabostat dose in cycles 1 and 2.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: PD-1/PD-L1 and/or CTLA-4 Inhibitor Treatment naïve | Immune-related Disease Control Rate Per iRECIST | 4 Participants |
| Cohort B: PD-1/PD-L1 and/or CTLA-4 Inhibitor Pretreated | Immune-related Disease Control Rate Per iRECIST | 5 Participants |
Secondary
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.
Time frame: From the first date of administration of the study drug to the date of data cut-off (January 7, 2024)
Population: To be evaluable for response, patients must have completed at least 9 weeks of treatment and received at least 70% of the total planned talabostat dose in cycles 1 and 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: PD-1/PD-L1 and/or CTLA-4 Inhibitor Treatment naïve | Overall Survival (OS) | 16.4 Months |
| Cohort B: PD-1/PD-L1 and/or CTLA-4 Inhibitor Pretreated | Overall Survival (OS) | 26.1 Months |
Secondary
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.
Time frame: 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
Population: To be evaluable for response, patients must have completed at least 9 weeks of treatment and received at least 70% of the total planned talabostat dose in cycles 1 and 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: PD-1/PD-L1 and/or CTLA-4 Inhibitor Treatment naïve | Progression-free Survival (PFS) by iRECIST | 2.7 Months |
| Cohort B: PD-1/PD-L1 and/or CTLA-4 Inhibitor Pretreated | Progression-free Survival (PFS) by iRECIST | 2.5 Months |
Secondary
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.
Time frame: 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
Population: To be evaluable for response, patients must have completed at least 9 weeks of treatment and received at least 70% of the total planned talabostat dose in cycles 1 and 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: PD-1/PD-L1 and/or CTLA-4 Inhibitor Treatment naïve | Progression-free Survival (PFS) by RECIST v1.1 | 2.7 Months |
| Cohort B: PD-1/PD-L1 and/or CTLA-4 Inhibitor Pretreated | Progression-free Survival (PFS) by RECIST v1.1 | 2.5 Months |
Secondary
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.
Time frame: 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.
Population: All patients who received at least one dose of study drug were included in safety analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: PD-1/PD-L1 and/or CTLA-4 Inhibitor Treatment naïve | Treatment-related Adverse Event (TRAE) | 10 Participants |
| Cohort B: PD-1/PD-L1 and/or CTLA-4 Inhibitor Pretreated | Treatment-related Adverse Event (TRAE) | 9 Participants |