Trial Title:
A Trial of BXCL701 and Pembrolizumab in Patients With mCRPC Either Small Cell Neuroendocrine Prostate Cancer or Adenocarcinoma Phenotype.
NCT ID:
NCT03910660
Condition:
Prostate Cancer
Neuroendocrine Tumors
Small Cell Carcinoma
Conditions: Official terms:
Prostatic Neoplasms
Adenocarcinoma
Neuroendocrine Tumors
Carcinoma, Small Cell
Small Cell Lung Carcinoma
Pembrolizumab
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Active, not recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
BXCL701 plus Pembrolizumab
Description:
BXCL701 tablets dosage strengths include 0.05mg and 1mg tablets for oral administration.
BXCL701 will be administered orally as 0.05mg and 1mg tablets. Patients will take the
prescribed number of tablets on Days 1 to 14 of each cycle, for a total daily dose of 0.4
mg, 0.6 mg, or an intermediate dose. BXCL701 will be continued until PD or unacceptable
toxicity, or closure of the study by the sponsor; no maximum duration of therapy has been
set.
BXCL701 should not be taken on an empty stomach.
On days when PD studies are being performed, BXCL701 should be administered at the study
center and should be administered at approx. the same time of day on each treatment day
in the cycle. In cycles in which PD are not evaluated, BXCL701 also should be
administered at approx. the same time of day on each treatment day.
The PEMBRO dose will be 200 mg, administered as an IV infusion over 30 mins. on Day 1 of
each 21-day cycle.
Arm group label:
Phase 1b
Arm group label:
Phase 2a
Arm group label:
Phase 2b combination
Other name:
BXCL701 plus Pembro
Intervention type:
Drug
Intervention name:
BXCL701 monotherapy
Description:
BXCL701 tablets dosage strengths include 0.05mg and 1mg tablets for oral administration.
BXCL701 will be administered orally as 0.05mg and 1mg tablets. Patients will take the
prescribed number of tablets on Days 1 to 14 of each cycle, for a total daily dose of 0.4
mg, 0.6 mg, or an intermediate dose. BXCL701 will be continued until PD or unacceptable
toxicity, or closure of the study by the sponsor; no maximum duration of therapy has been
set.
BXCL701 should not be taken on an empty stomach.
On days when PD studies are being performed, BXCL701 should be administered at the study
center and should be administered at approx. the same time of day on each treatment day
in the cycle. In cycles in which PD are not evaluated, BXCL701 also should be
administered at approx. the same time of day on each treatment day.
Arm group label:
Phase 2b monotherapy
Other name:
BXCL701
Summary:
An open-label, multicenter, Phase 1b/2 study to identify the recommended Phase 2 dose and
assess the efficacy and safety of BXCL701 administered orally, as monotherapy and in
combination with PEMBRO, in patients with mCRPC. Patients enrolled in the Phase 2a
portion of the study will have either Small Cell Neuroendocrine Prostate
Cancer(SCNC)(Cohort A) or adenocarcinoma phenotype (Cohort B), while the Phase 2b
randomized portion of the study will enroll only the histologic subtype(s) showing
preliminary evidence in Phase 2a. The study will also assess other efficacy parameters,
such as rPFS, PSA PFS, OS, and DOR, as well as the safety of the combined treatment. The
study will consist of three components.
Detailed description:
An open-label, multicenter, Phase 1b/2 study to identify the recommended Phase 2 dose and
assess the efficacy and safety of BXCL701 administered orally, as monotherapy and in
combination with PEMBRO, in patients with mCRPC. Patients enrolled in the Phase 2a
portion of the study will have either Small Cell Neuroendocrine Prostate
Cancer(SCNC)(Cohort A) or adenocarcinoma phenotype (Cohort B), while the Phase 2b
randomized portion of the study will enroll only the histologic subtype(s) showing
preliminary evidence in Phase 2a. The study will also assess other efficacy parameters,
such as rPFS, PSA PFS, OS, and DOR, as well as the safety of the combined treatment. The
study will consist of three components.
1. Phase 1b: Safety and tolerability of the combination of BXCL701 administered once
daily (QD) on Days 1 to 14 of a 21-day cycle plus PEMBRO 200 mg administered
intravenously (IV) on Day 1 of every 21 days will be assessed and confirmed in
patients with mCRPC. In the first cohort enrolled in the study, the initial dose
level of BXCL701 will be 0.4 mg; if there are no safety concerns, this will be
escalated to a total daily dose of 0.6 mg.
2. Phase 2a (Simon 2 Stage): Patients will be treated with BXCL701 in combination with
PEMBRO. Patients will be grouped in 1 of 2 cohorts based on phenotype.
- Cohort A: Patients with any Small Cell/Neuroendocrine features, either de novo
or treatment-emergent included mixed SCNC.
- Cohort B: Cohort B: Patients with adenocarcinoma and no evidence of small cell
or neuroendocrine features.
Phase 2b (for the histologic subtype[s] showing preliminary efficacy in Phase 2a):
Patients within a given subtype will be randomized 2:1 to receive either BXCL701 combined
with PEMBRO or BXCL701 monotherapy.
Phase 1b:
Patients will be observed for dose-limiting toxicity (DLT) during Cycle 1. Three patients
will be treated initially with BXCL701 0.4 mg plus PEMBRO:
- If there are no DLTs in Cycle 1, the dose of BXCL701 will be escalated to a total
daily dose of 0.6 mg in the next cohort of 3 patients.
- If ≥1 of the 3 original patients has a DLT in Cycle 1, after a discussion between
the sponsor and the investigator, either 3 patients (if 1 patient experiences a DLT)
or 6 to 9 patients (if 2 or 3 patients experiences a DLT) will be added at the 0.4
mg BXCL701 dose level. For this expanded 0.4 mg cohort:
- If none of the patients experience a DLT, consideration will be given to dose
escalation to BXCL701 0.6 mg plus PEMBRO
- If 1/3 of the patients experience a DLT, the Phase 2 can commence
- If >1/3 of the patients experience a DLT, a discussion will be held between the
investigators and sponsors as to how to proceed.
Following dose escalation to BXCL701 0.6 mg plus PEMBRO in 3 patients:
- If there are no DLTs at this dose level, the Phase 2a can commence.
- If ≥1/3 patients have a DLT in Cycle 1, after a discussion between the sponsor and
the investigator, 6 to 9 patients will be added at the 0.6 mg BXCL701 total daily
dose level; and consideration of an alternate dosing (e.g., split dose) schedule may
be given.
- For this additional cohort of 6 to 9 patients:
- If 1/3 of the patients experience a DLT, consideration will be given to the
use of a 0.4 mg total daily dose of BXCL701, or an intermediate dose, plus
PEMBRO in the Phase 2a.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
All patients must satisfy the following inclusion and exclusion criteria to be eligible
for entry into the trial.
1. Patient has evidence of progressive, metastatic castration-resistant disease, as
defined by PCWG3 criteria.
a. Patients with de novo small cell prostate cancer are not required to have
received androgen deprivation therapy (ADT).
2. Progression during or following completion of at least 1 prior line of systemic
therapy for locally advanced or metastatic prostate cancer.
3. Phases 2a and 2b Only:
SCNC - Cohort A of Phase 2a only:
1. Patient has histologic evidence of SCNC either with archival tissue or a fresh
tumor biopsy obtained during screening. Tumor biopsy tissue must be submitted
for a central laboratory pathology review; however, enrollment can proceed if
SCNC is determined by a local pathology review.
2. Patient has previously received at least 1 prior line of cytotoxic
chemotherapy. Patients who either have refused chemotherapy or are considered
unsuitable for chemotherapy may be eligible following discussion with the
sponsor.
3. Must be willing to undergo metastatic tumor biopsy during Screening.
Requirement may be waived in patients without safely accessible lesion or for
patients with evaluable archival metastatic tumor tissue
4. Has measurable disease per RECIST 1.1 criteria.
Adenocarcinoma - Cohort B of Phase 2a; randomized population for Phase 2b
1. Patient has histologically or cytologically confirmed adenocarcinoma of the
prostate without small cell neuroendocrine features.
2. Patients with soft tissue disease must provide a fresh core or excisional
biopsy or archival tissue from a site not previously irradiated for central
pathology review; however enrollment may proceed if predominant adenocarcinoma
without small cell neuroendocrine features is determined by local pathology
review.
3. Has been treated with at least 1 but no more than 2 second generation AR
pathway target agents (e.g., abiraterone acetate and/or enzalutamide or other
next generation agent) and at least 1 regimen/line of taxane containing
chemotherapy in the mCSPC or mCRPC setting. Patients with known actionable
mutations should have progressed on applicable standard care targeted therapy
or have documented intolerance to or be unsuitable for such therapy.
4. RECIST 1.1 measurable disease or detectable bone metastases by whole body bone
scintigraphy.
4. Patient has serum testosterone <50 ng/dL during Screening except for those with de
novo small cell prostate cancer.
a. Patients with treatment-emergent SCNC without a history of bilateral orchiectomy
are required to remain on luteinizing hormone-releasing hormone (LHRH) analog during
the course of protocol therapy except for patients with de novo small cell prostate
cancer.
5. Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
6. Patient is ≥18 years of age.
7. Patient's acute toxic effects of previous anticancer therapy have resolved to ≤Grade
1 except for Grade 2-3 peripheral neuropathy or any grade of alopecia.
8. Patient has adequate baseline organ function, as demonstrated by the following:
1. Serum creatinine ≤1.5 times institutional upper limit of normal (ULN) or
calculated creatinine clearance >50 mL/min;
2. Serum albumin ≥2.5 g/dL;
3. Total bilirubin ≤1.5 × ULN;
4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 ×
institutional ULN (patients with hepatic metastases must have AST/ALT ≤5 ×
ULN).
9. Patient has adequate baseline hematologic function, as demonstrated by the
following:
1. Absolute neutrophil count (ANC) ≥1.5 × 109/L.
2. Hemoglobin ≥8 g/dL and no red blood cell transfusions during the prior 14 days.
3. Platelet count ≥100 × 109/L and no platelet transfusions during the prior 14
days.
10. Male patients and their female partners of childbearing potential must agree and
commit to use a barrier contraception throughout the duration of the study until at
least 6 months 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 6 months 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.
Exception: In the United States, female partners of study participants are not
required to use contraception as a condition of their partners' eligibility, but
female partners with child bearing potential should consider use of effect methods
of contraception for the duration of their male partners' study participation and
for at least 6 months following the last dose of study medication.
11. Patient has signed informed consent prior to initiation of any study-specific
procedures or treatment.
12. Patient is able to adhere to the study visit schedule and other protocol
requirements, including follow-up for overall survival (OS).
Exclusion Criteria:
1. Patient has received treatment with >2 cytotoxic chemotherapy regimens for
castration-resistant prostate cancer (CRPC). Chemotherapy in the hormone-sensitive
setting does not count in this assessment provided the last dose was >6 months
before study entry. A change in chemotherapy agents due to intolerance after brief
exposure may not count in this assessment, pending review with Medical Monitor.
2. 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.
3. Patient has received treatment with an investigational systemic anticancer agent
within 14 days prior to study drug administration.
4. Patient has received prior treatment with an anti-PD-1, anti-PD-L1, anti-programmed
death ligand 2 (PD-L2) agent or with an agent directed to another co-inhibitory
T-cell receptor (e.g., cytotoxic T lymphocyte-associated antigen 4 [CTLA-4], OX-40,
CD137) or requires concomitant treatment with DPP4 inhibitors.
5. Patient has an additional active malignancy that may confound the assessment of the
study endpoints. If the patient has a past cancer history (active malignancy within
2 years prior to study entry) with substantial potential for recurrence, this must
be discussed with the sponsor before study entry. Patients with the following
concomitant neoplastic diagnoses are eligible: non-melanoma skin cancer and
carcinomas in situ (including transitional cell carcinoma, anal carcinoma, and
melanoma in situ).
6. 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).
7. QT interval corrected for heart rate using Bazett's formula (QTcB) >480 msec at
Screening.
8. Patient has uncontrolled, clinically significant pulmonary disease (e.g., chronic
obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the
investigator would put the patient at significant risk for pulmonary complications
during the study.
9. Patient has brain or leptomeningeal metastases that are symptomatic and progressive
on imaging. Patients with a history of central nervous system (CNS) metastases must
have received appropriate treatment. Central nervous system imaging is not required
prior to study entry unless there is a history of CNS involvement or clinical
suspicion of CNS involvement. Imaging of patients with a prior history of CNS
metastases should be compared to prior imaging to discern disease progression.
10. Patient has an active autoimmune disease or Grade ≥3 non-infectious pneumonitis that
has required systemic treatment in the past 2 years (i.e., with use of disease
modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy
(e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for
adrenal or pituitary insufficiency) or treatment with drugs (e.g., neomercazol,
carbimazole) that function to decrease the generation of thyroid hormone by a
hyperfunctioning thyroid gland (e.g., in Graves' disease) is not considered a form
of systemic treatment of an autoimmune disease.
11. 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).
12. Patient has uncontrolled intercurrent illness including, but not limited to,
uncontrolled infection, suspected or active SARS-CoV-2 (COVID-19) infection,
disseminated intravascular coagulation, or psychiatric illness/social situations
that would limit compliance with study requirements.
13. Patient has known positive status for human immunodeficiency virus, active or
chronic Hepatitis B, or Hepatitis C. Screening is not required.
14. Patient has any medical condition which, in the opinion of the investigator, places
the patient at an unacceptably high risk for toxicity.
15. Any dysphagia, odynophagia, esophageal dysmotility or stricture, known GI
malabsorption syndrome, or intractable diarrhea that may significantly alter the
absorption of orally administered study drug.
16. Patients with history of symptomatic orthostatic hypotension within 3 months prior
to enrollment. Orthostatic hypotension is defined as a drop in systolic blood
pressure (BP) of ≥ 20 mmHg or diastolic BP of ≥ 10 mmHg with assumption of an
upright posture.
Gender:
Male
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
University of California San Francisco (UCSF)
Address:
City:
San Francisco
Zip:
94158
Country:
United States
Facility:
Name:
BioXcel Clinical Research Site
Address:
City:
Denver
Zip:
80211
Country:
United States
Facility:
Name:
Yale University
Address:
City:
New Haven
Zip:
06510
Country:
United States
Facility:
Name:
Moffitt Cancer Center and Research Institute
Address:
City:
Tampa
Zip:
33612
Country:
United States
Facility:
Name:
BioXcel Clinical Research Site
Address:
City:
Detroit
Zip:
48201
Country:
United States
Facility:
Name:
Center for Advanced Medicine / R.J. Zuckerberg Cancer Center (Northwell Health Cancer Institute)
Address:
City:
Lake Success
Zip:
11042
Country:
United States
Facility:
Name:
Weill Cornell Medicine New York
Address:
City:
New York
Zip:
10021
Country:
United States
Facility:
Name:
White Plains Hospital Center for Cancer Care
Address:
City:
White Plains
Zip:
10601
Country:
United States
Facility:
Name:
The Ohio State University
Address:
City:
Columbus
Zip:
43210
Country:
United States
Facility:
Name:
BioXcel Clinical Research Site
Address:
City:
Glasgow
Zip:
G12 0YN
Country:
United Kingdom
Facility:
Name:
BioXcel Clinical Research Site
Address:
City:
London
Zip:
W1T 7HA
Country:
United Kingdom
Facility:
Name:
BioXcel Clinical Research Site
Address:
City:
Sutton
Zip:
SM2 5NG
Country:
United Kingdom
Start date:
February 12, 2019
Completion date:
December 2025
Lead sponsor:
Agency:
BioXcel Therapeutics Inc
Agency class:
Industry
Source:
BioXcel Therapeutics Inc
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT03910660
