Docetaxel in Combination with Cirmtuzumab for Treatment of Metastatic Castration Resistant Prostate Cancer
This phase Ib trial tests the safety, effectiveness, and best dose of docetaxel in combination with cirmtuzumab for the treatment of castration resistant prostate cancer that has spread to other places in the body (metastatic). Docetaxel is in a class of medications called taxanes. It stops cancer cells from growing and dividing and may kill them. Cirmtuzumab is a monoclonal antibody that binds to a receptor called ROR1, which may contribute to prostate cancer growth. Blocking this receptor may interfere with the ability of cancer cells to grow and spread. Giving cirmtuzumab in combination with docetaxel may be more effective at stopping cancer cells from growing than giving either drug alone.
Inclusion Criteria
- Participants must be male aged >= 18 years of age
- Participants must have histologically or cytologically confirmed adenocarcinoma of the prostate. Patient with neuroendocrine differentiation are allowed to enroll
- 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 as defined by a serum testosterone < 50 ng/dL and at least one of the following (patients with non-measurable disease only are eligible): * Castrate resistant disease as defined by PCWG-3 criteria. Participants must have a rise in PSA on two successive determination at least one week apart and PSA levels >= 2 ng/mL * Soft tissue progression as defined by RECIST version 1.1 * Bone disease progression as defined by PCWG-3 criteria including the development of two or more new lesions on bone scan
- Participants must have tumor accessible for biopsy and be agreeable to tumor biopsy. A metastatic focus is preferred but if not available and prostate is still intact, prostate biopsy can be performed
- Availability of formalin-fixed, paraffin-embedded (FFPE) archival tumor specimens, when available
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 80%)
- White blood cell count (WBC) >= 3,000/mcL (within 28 days prior to registration)
- Absolute neutrophil count (ANC) >= 1,500/mcL (within 28 days prior to registration)
- Platelets >= 100,000/mcL (within 28 days prior to registration)
- Hemoglobin >= 9 g/dL (without transfusions 14 days prior to registration) (within 28 days prior to registration)
- Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN). For subjects with Gilbert’s disease =< 3.0 mg/dL (within 28 days prior to registration)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x institutional ULN (within 28 days prior to registration)
- Creatinine clearance >= 40 ml/min as defined by Cockcroft-Gault equation (within 28 days prior to registration)
- The effects of cirmtuzumab and docetaxel on the developing human fetus are unknown. For this reason, men treated or enrolled on this protocol must agree to use two highly effective forms of contraception and avoid sperm donation prior to the study, for the duration of study participation, and six months after discontinuation of study treatment
- Ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making who have a legal guardian (e.g., spouse) able to make informed decisions on behalf of the patient are eligible
Exclusion Criteria
- No pure small cell carcinoma of the prostate
- Prior treatment with cirmtuzumab
- 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
- Prior hemibody external radiotherapy
- 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. Patients treated with surgery or radiation and are stable for at least 4 weeks following treatment are eligible
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring need for intravenous anti-microbials, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Treatment with antimicrobial agent within 4 weeks of treatment initiation
- Clinically significant medical condition defined as: * Cerebral infarction within 6 months of study treatment * Transient ischemic attack within 3 months of study treatment * Myocardial infarction within 6 months of study treatment * Uncontrolled angina within 3 months of study treatment * Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the past, or history of anthracycline or anthracenedione (mitoxantrone) treatment, unless an echocardiogram performed within 3 months of the screening visit results in a left ventricular ejection fraction that is >= 45% * History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsade de pointes) * Family history of long QT syndrome * History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place * Uncontrolled hypertension as indicated by a resting systolic blood pressure >170 mmHg or diastolic blood pressure >105 mmHg at the screening visit * History of hypertensive emergency or encephalopathy within 6 months of study treatment * Deep venous thrombosis or pulmonary embolism within 3 months of study treatment * History of abdominal fistula, intra-abdominal abscess, or gastrointestinal perforation within the 3 months of study treatment * Known active hepatitis B, C or human immunodeficiency viruses (HIV)
- Major surgery within 4 weeks of study treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to docetaxel or cirmtuzumab
- Individuals with a history of a different malignancy are ineligible except for the following: 1) if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy, or 2) individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: superficial bladder cancer, basal cell or squamous cell carcinoma of the skin
- Patient has a history of non-compliance or other medical illness that would preclude compliance with study procedures
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT05156905.
PRIMARY OBJECTIVE:
I. To determine the recommended phase 2 dose of docetaxel combined with zilovertamab (cirmtuzumab) in patients with metastatic castration resistant prostate cancer (CRPC).
SECONDARY OBJECTIVES:
I. To determine the composite endpoint of clinical benefit defined as any one of the following: prostate specific antigen (PSA) response by Prostate Cancer Working Group (PCWG)-3 criteria, objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and stable disease > 6 months by RECIST version 1.1.
II. To determine the safety and tolerability of docetaxel combined with cirmtuzumab in patients with metastatic CRPC defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5 grading.
III. To evaluate total alkaline phosphatase response defined as a reduction of >= 30% from the baseline value, confirmed >= 4 weeks later.
IV. To determine time to PSA progression as defined by PCWG-3 criteria.
V. To evaluate 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.
VI. To determine radiographic progression-free survival (PFS).
VII. To evaluate time to first subsequent anti-cancer therapy (including androgen receptor signaling agents, cytotoxic chemotherapy, immunotherapy, or investigational agents) or death.
VIII. To evaluate time to first symptomatic skeletal event (SSE) defined as 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.
IX. To evaluate overall survival (OS).
EXPLORATORY OBJECTIVES:
I. To evaluate efficacy parameters (objective response rate, PSA response, stable disease > 6 months) in predefined subgroups:
Ia. Patients with and without prior docetaxel use for CRPC.
Ib. Patients with 0, 1 or 2+ CRPC directed therapies.
Ic. Patients with or without visceral metastases.
II. To evaluate expression of ROR1 by immunohistochemistry (IHC) in pre-, on-treatment and post-therapy biopsy.
III. To correlate ROR1 IHC status and ROR1 signaling with efficacy parameters (objective response rate, PSA response, stable disease > 6 months, radiographic PFS).
IV. To evaluate tissue-based molecular and proteomic markers of response and resistance to therapy.
V. To evaluate blood-based (circulating tumor cells [CTCs] and immune cells) biomarkers of response and resistance to therapy.
VI. To evaluate germline mutation status in enrolled patients.
VII. To evaluate family history of cancers in the study population.
VIII. To evaluate and compare the cancer microbiome in tumor tissue, fecal material, urine, and blood.
OUTLINE:
Patients receive cirmtuzumab intravenously (IV) over 30-90 minutes on days 1, 15, and 29 of cycle 1. Beginning in cycle 2, patients receive cirmtuzumab IV over 30-90 minutes and docetaxel IV on day 1 of each cycle. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 8, patients receive cirmtuzumab IV over 30-90 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo biopsy at baseline, weeks 6-8, and at the end of treatment.
After completion of study treatment, patients are followed up at 42 days and then every 6 months for up to 5 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationUC San Diego Medical Center - Hillcrest
Principal InvestigatorRana Ramzi McKay
- Primary IDUCSD 191541
- Secondary IDsNCI-2022-05659
- ClinicalTrials.gov IDNCT05156905