| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Small Cell Neuroendocrine Prostate Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060862 |
| E.1.2 | Term | Prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objectives of the study are:
To estimate the composite response rate of the combination of BXCL701 + PEMBRO in Cohort A and B, respectively. Composite response rate is defined as achieving 1 or more of the following:
o Objective response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
o Circulating tumor cell (CTC) conversion from >5/7.5 mL to <5/7.5 mL per Veridex assay by completion of Week 12 of protocol therapy.
o Greater than 50% prostate-specific antigen (PSA) decline from baseline by completion of Week 12 of protocol therapy. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study include:
• To estimate the average radiographic progression-free survival (rPFS) of the combination of BXCL701 and PEMBRO in Cohort A and B.
• To estimate the average progression-free survival (PSA PFS) of the combination of BXCL701 and PEMBRO in Cohort A and B.
• To estimate the median overall survival (OS) of the combination of BXCL701 and PEMBRO in Cohort A and B.
• To estimate the median duration of response (DOR) of the combination of BXCL701 and PEMBRO in Cohort A and B.
• To continue to characterize the safety profile of BXCL701 in combination with PEMBRO.
• To assess population pharmacokinetics of BXCL701 i.e. how the drug is carried within the body of patients
• To assess the pharmacodynamic profile of the combination of BXCL701 and PEMBRO by measuring relevant effects
on targets previously shown to be modulated by BXCL701 in humans. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient has evidence of progressive mCRPC as defined by PCWG3 criteria.
2. Progression during or following completion of at least 1 prior line of systemic therapy for locally advanced or metastatic prostate cancer.
a. Patients with de novo small cell prostate cancer are not required to have received androgen deprivation therapy (ADT).
3. Efficacy Stage only:
For Cohort A (SCNC):
a. Patient has histologic evidence of SCNC either with archival tissue or a fresh tumor biopsy obtained during Screening. Archival or fresh 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. (Central pathology review is optional for patients enrolled in the lead-in.)
b. 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.
c. 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.
d. Has measurable disease per RECIST 1.1 criteria.
For Cohort B (Adenocarcinoma):
a. Patient has histologically or cytologically confirmed adenocarcinoma of the prostate without small cell neuroendocrine features.
b. Patients with soft tissue disease must provide a fresh core or excisional biopsy or archival tissue obtained ≤ 3mo prior to study start 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.
c. 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 metastatic castration-sensitive prostate cancer (mCSPC) or mCRPC setting. Patients with known actionable mutations should have progressed applicable standard care targeted therapy or have documented intolerance to or be unsuitable for such therapy.
d. 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 an 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:
a. Serum creatinine (Cr) ≤1.5 times institutional upper limit of normal (ULN) or calculated Cr clearance >50 mL/min.
b. Serum albumin ≥2.5 g/dL.
c. Total bilirubin ≤1.5 × ULN.
d. 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:
a. Absolute neutrophil count (ANC) ≥1.5 × 109/L;
b. Hemoglobin ≥8 g/dL and no red blood cell transfusions during the prior 14 days;
c. 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 (e.g., condom with spermicidal foam/gel/film/cream/ suppository) 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. [Note: In the United States, female partners of study participants are not required to use contraception as a condition of their partner’s eligibility, but female partners with child bearing potential should consider use of effective methods of contraception for the duration of their male partner’s 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 OS. |
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| E.4 | Principal 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 (e.g., gliptins).
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. Patient has 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 CNS metastases must have received appropriate treatment. CNS 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, etc.) 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 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. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The Stage 1 analysis will be performed for Cohort A and Cohort B, separately. In each cohort, when 15 patients have completed approximately 6 cycles of treatment and have 2 post-baseline tumor assessments and PSA or CTC measurements, the number of patients who meet the composite response criteria of achieving 1 or more the following: 1) objective response by RECIST 1.1 criteria, 2) ≥50% decline from baseline in serum PSA by Week 12 of treatment, or 3) CTC conversion from >5/7.5 mL to <5/7.5 mL per Veridex assay by completion of Week 12 of protocol therapy will be evaluated. Using minimax 2-stage Simon design, if 2 or fewer out of 15 stage 1 patients meet at least 1 of the composite response criteria, enrollment will be stopped. This will indicate that data to date are consistent with the null hypothesis that the composite response rate is 15% or less, thereby rejecting the alternative hypothesis that the composite response rate is 35%. If 3 or more out 15 patients meet at least 1 of the composite response criteria, 13 more patients will be enrolled and treated to proceed to stage 2, for a total of 28 patients in both stages.
In each Cohort enrolling in Stage 2, when the additional 13 patients enrolled and treated in Stage 2 have completed approximately 6 cycles of treatment, 2 post-baseline assessments of tumor, and PSA and CTCs measurements, the number of patients who meet at least 1 of the 3 criteria for the composite endpoint will be evaluated. If the total number of patients who meet the composite endpoint in 28 patients in both stages is 7 or less, then data are consistent with the null hypothesis of composite endpoint rate of 15% or lower with nominal 0.05 1-sided significance level. If the number of patients who meet the composite endpoint is 8 or more, then the data are consistent with the composite endpoint rate of at least 35%. The composite endpoint rate across 2 stages and its exact 95% confidence interval (CI) will be calculated as if data are collected in a single stage. This approach that ignores the sequential statistical testing may lead to biased point estimate of the composite endpoint rate and the CI may not provide the stated coverage probability, but is generally accepted when the event rate is relatively small.
The composite endpoint rate will also be calculated for the ITT analysis population. Patients in the ITT population with missing composite endpoint will be considered nonresponders (e.g., not 1 of the 3 criteria for composite endpoint is met). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Stage 1: When 15 patients have completed approximately 6 cycles.
Stage 2: when additional 13 patients enrolled and treated in each cohort have completed approximately 6 cycles of treatment. |
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| E.5.2 | Secondary end point(s) |
Analysis of Secondary Parameter(s): Time-to-Event Response
The distribution of time-to-event response including rPFS, PSA PFS, DOR, and OS will be estimated by Kaplan-Meier methodology. The medians of these time-to-event efficacy responses, if available, and their 2-sided 95% CI, will be reported. In addition, the proportions of patients with events at selected time points, together with their 2-sided 95% CI will be presented. The calculations will be performed based on fixed sample, single stage design. The primary analysis will be performed using the ITT analysis population. As a supplement, time-to-event analysis will be performed using the response evaluable analysis population.
Analyses on duration of overall objective response will be performed for all ITT analysis population who achieve confirmed PR or CR. The number of CR and PR patients may be small, and thereby limit use of the Kaplan-Meier method to provide reliable information. In this case, descriptive statistics or listings will be provided. After discontinuing the study medication, patients may be treated with additional therapy. Data collected after patients have been treated with additional therapy will not be used to evaluate the duration of objective response.
Analysis of Secondary Endpoints: DPP Activity and Cytokine Levels
The analysis of the secondary efficacy endpoints including DPP activity and cytokine levels will be reported for the PD analysis population. The proportion of patients who exhibit DPP activity will be reported and descriptive statistics for
levels of cytokines previously shown to be modulated by BXCL701 in human will be reported. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The analysis of the secondary efficacy endpoints including DPP activity and cytokine levels will be reported for the PD analysis population. The proportion of patients who exhibit DPP activity will be reported and descriptive statistics for levels of cytokines previously shown to be modulated by BXCL701 in human will be reported.
These evaluations will take place at the end of the study, after all data is available for the PD analysis population. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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