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Pembrolizumab

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Immune Checkpoint Inhibitors

Patients will be observed for dose-limiting toxicity (DLT) during Cycle 1. 3 patients will be treated initially with 0.4 mg BXCL701 plus PEMBRO:

If there are no DLTs, the dose of BXCL701 will be escalated to 0.6 mg in the next cohort.

If ≥1/3 of patients has a DLT in Cycle 1, either 3 patients (if 1 experience a DLT) or 6 to 9 patients (if 2 or 3 experiences a DLT) will be added at the 0.4 mg dose.

At the 0.4mg dose:

If \<1/3 of the patients experience a DLT, consideration will be given to dose to 0.6 mg BXCL701 plus PEMBRO.

If 1/3 of the patients experience a DLT, the Phase 2a can commence. If \>1/3 of the patients experience a DLT, a discussion will be held as to how to proceed.

Following 0.6 mg dose. If there are no DLTs, the Phase 2a can commence. If ≥1/3 patients have a DLT in Cycle 1, after a discussion, 6 to 9 patients will be added at the 0.6 mg dose.

For this cohort of 6 to 9 patients:

If \</=1/3 of the patients experience a DLT, the Phase 2a can commence

After assessment of the safety and confirmation of the BXCL701/+PEMBRO dose schedule to be used in the subsequent stage, the Phase 2a will begin. Eligible patients will receive BXCL701 QD on Days 1 to 14 of a 21-day cycle plus PEMBRO 200 mg administered IV on Day 1 every 21 days.

Upon completion of the Phase 2a and achievement of the protocol required composite responses for a given histologic subtype, the Phase 2b enrollment will begin for that subtype. Eligible patients will be randomized to receive:

• Combination therapy of BXCL701 on Days 1 to 14 of a 21-day cycle plus PEMBRO 200 mg administered IV on Day 1 of every 21 days.

Upon completion of the Phase 2a and achievement of the protocol required composite responses for a given histologic subtype, the Phase 2b enrollment will begin for that subtype. Eligible patients will be randomized to receive:

* Monotherapy BXCL701 on Days 1 to 14 of a 21-day cycle. Upon radiographic disease progression with monotherapy, crossover to combination treatment is allowed.

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.

BXCL701 plus Pembrolizumab

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.

BXCL701 monotherapy

Amir Hafeez, MD

Vincent O'Neill, MD

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.

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, the Phase2a can commence.
  * 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.

A Trial of BXCL701 and Pembrolizumab in Patients With mCRPC Either Small Cell Neuroendocrine Prostate Cancer or Adenocarcinoma Phenotype.

Phase 1b/2 Study of BXCL701, a Small Molecule Inhibitor of Dipeptidyl Peptidases, Administered in Combination With the Anti-Programmed Cell Death 1 Monoclonal Antibody Pembrolizumab in Patients With mCRPC Either Small Cell Neuroendocrine Prostate Cancer or Adenocarcinoma Phenotype

Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria; circulating tumor cell (CTC) conversion from \>5/7.5 mL to \<5/7.5 mL per Veridex assay; and 50% or greater prostate-specific antigen (PSA) decline from baseline.

To evaluate the response rates, defined by RECIST 1.1 criteria, by histologic subtype in patients treated with the combination of BXCL701 + PEMBRO and with BXCL701 monotherapy.

The median time frame with progression-free survival with the use of BXCL701 in combination with Pembro determined by radiographic evidence.

The median time frame with progression-free survival with the use of BXCL701 in combination with Pembro

The median time frame with overall survival with the use of BXCL701 in combination with Pembro

The timeframe in which the tumor reacts to BXCL701 in combination with Pembro

Determines the frequency and severity of known and unknown adverse events with the use of BXCL701 in combination with Pembro

To assess the population pharmacokinetics of BXCL701 using sparse pharmacokinetic sampling.

To assess the pharmacodynamic profile of the combination of BXCL701 and PEMBRO by measuring relevant effects on those cytokines previously shown to be modulated by BXCL701 in humans.

To estimate the CRR, OS, duration of response, rPFS, and PSA PFS of the BXCL701 + PEMBRO combination and monotherapy in Cohort A and B, respectively. Composite response rate is defined as achieving 1 or more of the following:

* Objective response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
* 50% or greater PSA decline from baseline.

Spots Global Cancer Trial Database for bxcl701 plus pembrolizumab