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.
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
