Study of Docetaxel Combined With Cirmtuzumab in Metastatic Castration Resistant Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to examine the safety and efficacy of cirmtuzumab in combination with standard of care docetaxel in patients with metastatic castration resistant prostate cancer. Docetaxel is a taxane chemotherapy which has been shown to prolong survival in men with castration resistant prostate cancer. Cirmtuzumab is a monoclonal antibody that targets the receptor called ROR1 of the non-canonical Wnt pathway and is suspected to contribute to prostate cancer growth and progression.

Detailed Description
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This study seeks to targeting the non-canonical Wnt pathway with an antibody against ROR1. ROR1 is an attractive target given its low expression in non-malignant tissues and its role in proliferation and survival in prostate cancer. From preclinical data in a variety of tumor types, blockade of ROR1 inhibits cell growth and cirmtuzumab has shown efficacy in clinical trials with CLL. Preclinical data suggests that ROR1 is upregulated in chemotherapy resistant cells and treatment with cirmtuzumab and a taxane achieved higher cytotoxic response than both agents alone, supporting the use of the combination of cirmtuzumab and a taxane. Based on the biological rationale behind cirmtuzumab and preclinical activity with docetaxel, this is an open label, phase 2 clinical trial to evaluate the safety and efficacy of cirmtuzumab in combination with docetaxel for the treatment of metastatic, castrate resistant prostate adenocarcinoma.

Official Title
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A Phase 1b Trial Investigating Docetaxel Combined With Cirmtuzumab in Patients With Metastatic Castration Resistant Prostate Cancer

Conditions
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Metastatic Castration-resistant Prostate Cancer

Intervention / Treatment
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* Drug: Cirmtuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have histologically or cytologically confirmed adenocarcinoma of the prostate. Patients with neuroendocrine component are eligible. Participants must have castrate levels of serum testosterone < 50 ng/dL. Participants without orchiectomy must be maintained on luteinizing hormone releasing hormone (LHRH) agonist/antagonist. Participants must have received prior abiraterone and/or next generation androgen receptor antagonist (enzalutamide, apalutamide, or darolutamide) for hormone sensitive disease or CRPC. Prior docetaxel for hormone sensitive disease is permitted. Participants must have progressive disease. Patients with non-measurable disease are eligible. Eastern Cooperative Oncology Group performance status ≤1 (Karnofsky ≥80%). Patients must have normal organ and marrow function. Exclusion Criteria: No pure small cell carcinoma. Prior treatment with cirmtuzumab. No prior treatment with docetaxel for CRPC. Treatment with abiraterone, apalutamide, or darolutamide within 2 weeks of treatment initiation. Treatment with cytotoxic chemotherapy within 3 weeks of treatment initiation. Treatment enzalutamide or other investigational prostate cancer directed therapy within 4 weeks of treatment initiation. Palliative radiation therapy to the bone or other sites within 2 weeks of treatment initiation. Imminent or established spinal cord compression based on clinical and/or imaging findings. Known active central nervous system metastases and/or carcinomatous meningitis. Uncontrolled intercurrent illness or clinically significant medical condition. Treatment with antimicrobial agent within 4 weeks of treatment initiation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cirmtuzumab + Docetaxel<br>There is only one treatment arm on this study. The combination of cirmtuzumab + docetaxel will be administered on one treatment arm. Treatment will cirmtuzumab will be administered initially as a loading dose alone on days 1, 15, and 29 of cycle 1. Following the loading, cirmtuzumab will be given on Day 1 of every 21-day cycle starting on Cycle 2 to up to Cycle 7 corresponding with concurrent docetaxel administration. Following discontinuation or completion of docetaxel, treatment with cirmtuzumab will be continued Day 1 of every 28 cycle until disease progression, toxicity or study withdrawal. Docetaxel will be administered on day 1 of every 21-day cycle starting Cycle 2 for up to 6 cycles. | Drug: Cirmtuzumab<br>* Cirmtuzumab will be given in combination with docetaxel.<br>* Other names: Docetaxel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended phase 2 dose of docetaxel combined with cirmtuzumab | Defined by CTCAE version 5 grading | Patients will be followed from study entry to death or date last known alive, assessed up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events | Defined by CTCAE version 5 grading | Patients will be followed from study entry to death or date last known alive, assessed up to 36 months | 
| Total alkaline phosphatase response | Defined as a reduction of ≥30% from the baseline value, confirmed ≥4 weeks later. | Patients will be followed from study entry to death or date last known alive, assessed up to 36 months | 
| Time to PSA progression | Defined by PCWG-3 criteria | Patients will be followed from study entry to death or date last known alive, assessed up to 36 months | 
| Time to increase in the total alkaline phosphatase level | Defined as an increase of ≥25% from baseline at ≥12 weeks, in patients with no decrease from baseline, or as an increase of ≥25% above the nadir, confirmed ≥3 weeks later, in patients with an initial decrease from baseline. | Patients will be followed from study entry to death or date last known alive, assessed up to 36 months | 
| Radiographic progression free survival | Defined by PCWG-3 criteria for bone metastases and RECIST version 1.1 for soft tissue | Patients will be followed from study entry to death or date last known alive, assessed up to 36 months | 
| Time to first subsequent anti-cancer therapy | Time from study discontinuation to initiation of subsequent systemic anti-cancer therapy or death | Patients will be followed from study entry to death or date last known alive, assessed up to 36 months | 
| Time to first symptomatic skeletal event | Time to first symptomatic pathologic fracture, radiation to the bone given symptomatic bone metastasis, surgery to the bone given symptomatic bone metastasis, or symptomatic spinal cord compression | Patients will be followed from study entry to death or date last known alive, assessed up to 36 months | 
| Overall survival | Time from enrollment to death or last follow up | Patients will be followed from study entry to death or date last known alive, assessed up to 36 months | 
| Composite clinical benefit | Composite endpoint of clinical benefit defined as any one of the following: PSA response by PCWG3 criteria, objective response rate by RECIST version 1.1, and stable disease > 6 months by RECIST version 1.1. | Patients will be followed from study entry to death or date last known alive, assessed up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate cancer, Docetaxel, Wnt pathway, Cirmtuzumab, ROR1