Cixutumumab and Temsirolimus in Treating Patients With Metastatic Prostate Cancer

Study Overview
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Brief Summary
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This phase I/II trial is studying the side effects of giving cixutumumab together with temsirolimus and to see how well it works in treating patients with metastatic prostate cancer. Monoclonal antibodies, such as cixutumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving cixutumumab together with temsirolimus may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To confirm the safety and tolerability of IMC-A12 (cixutumumab) and temsirolimus using the recommended phase II dose level for advanced solid tumors in chemo-naive patients with metastatic castration-resistant prostate cancer and a rising prostate-specific antigen (PSA). (Phase I) II. To confirm the safety and tolerability of IMC-A12 and temsirolimus given on an every three weeks dosing schedule. (Phase I Extension) II. To determine the tumor response rate and/or composite time to progression (cTTP) for chemotherapy-naive patients with castration-resistant prostate cancer (CRPC) receiving the combination of IMC-A12 and CCI-779 (temsirolimus). (Phase II) SECONDARY OBJECTIVES: I. To determine the maximal percent decrease in PSA from baseline. II. To determine the change in PSA doubling time (PSADT). III. To determine the time to PSA progression and 6-month progression-free survival (PFS). IV. To determine the rate of adverse events. EXPLORATORY OBJECTIVES: I. To evaluate changes in circulating tumor cell (CTC) numbers with time. II. To evaluate IGF1R and androgen receptor (AR) in CTCs and correlate with response. III. To evaluate profiling CTCs at the molecular level by polymerase chain reaction (PCR) for prostate cancer-specific genes. IV. To explore the association between clinical outcomes, administration of therapy, and serial fludeoxyglucose F 18 (FDG)-positron emission tomography (PET) imaging. V. To correlate fluorine F 18 FMDHT (18-FDHT)-PET imaging findings with outcome measures of response. VI. To perform tumor biopsies and evaluate biomarkers that may correlate with active feedback and tumor response to therapy, including anti-insulin receptor substrate 1 (IRS-1), anti-IRS-2, phosphorylated (p) protein kinase B (Akt)(S473), p-ribosomal protein S6 kinase (70/S6K), anti-phospho-AKT1 substrate 1 (proline-rich) (PRAS 40), and phosphatase and tensin homolog gene (PTEN) status. OUTLINE: This is a multicenter study. Patients receive cixutumumab intravenously (IV) over 60-70 minutes and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 4 weeks.

Official Title
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Phase I/II Trial of Anti-IGF-IR Monoclonal Antibody IMC-A12 Plus mTOR Inhibitor Temsirolimus (CCI-779) in Metastatic Castration-Resistant Prostate Cancer (CRPC)

Conditions
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Hormone-Resistant Prostate Cancer, Prostate Adenocarcinoma, Recurrent Prostate Carcinoma, Stage IV Prostate Cancer

Intervention / Treatment
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* Biological: Cixutumumab
* Other: Diagnostic Laboratory Biomarker Analysis
* Drug: Temsirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the prostate Distant metastases evaluable by radionuclide bone scan, CT scan, or magnetic resonance imaging (MRI) within the past 28 days Evidence of progressive disease during androgen-deprivation therapy (including a trial of antiandrogen-withdrawal therapy), as defined by ≥ 1 of the following criteria: Progressive measurable disease using conventional solid tumor criteria Bone scan progression, defined as ≥ 2 new lesions on bone scan Increasing PSA, defined as ≥ 2 consecutive rising PSA values over a reference value taken ≥ 1 week apart (the third PSA value must be greater than the second PSA value, if not, a fourth PSA value must be greater than the second PSA value) Castrate levels of serum testosterone (i.e., ≤ 50 ng/dL) No known brain metastases Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 OR Karnofsky PS 70-100% Life expectancy > 6 months Leukocytes ≥ 3,000/μL Absolute neutrophil count (ANC) ≥ 1,500/μL Platelet count ≥ 100,000/μL Hemoglobin ≥ 9 g/dL Total bilirubin ≤ 2 times upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN Serum creatinine ≤ 1.5 times ULN Creatinine clearance ≥ 50 mL/min Able to adhere to the study visit schedule and other study requirements Fertile patients must use effective contraception before, during, and for 3 months after completion of study treatment Adequate lung function (pulmonary function test ≥ 70% for diffusion capacity of the lung for carbon monoxide [DLco]) No poorly controlled diabetes mellitus Patients with a history of diabetes are eligible provided their blood glucose is normal (i.e., fasting blood glucose < 120 mg/dL or < ULN) and they are on a stable dietary or therapeutic regimen No other malignancy within the past 3 years except for treated basal cell or squamous cell carcinoma of the skin or superficial transitional cell carcinoma of the bladder No uncontrolled major illness including, but not limited to, any of the following: Active infection, including human immunodeficiency virus (HIV) infection or viral hepatitis Symptomatic congestive heart failure (class III or IV) Unstable angina pectoris Myocardial infarction or acute coronary syndrome within the past year Serious cardiac arrhythmia Significant lung disease Major psychiatric illness No other concurrent anticancer agents or treatments No prior chemotherapy, except for neoadjuvant chemotherapy No prior anti-insulin-like growth factor receptor (IGFR) agents or mammalian target of rapamycin (mTOR) inhibitors No prior strontium-89, rhenium-186, rhenium-188, or samarium-153 radionucleotide therapy Prior standard-dose radiotherapy to the pelvis for prostate cancer and/or additional external-beam radiotherapy to metastatic sites allowed More than 4 weeks since prior surgery, radiotherapy, combined androgen blockade (excluding single-agent gonadotropin releasing-hormone agonists/antagonists), or investigational therapies No concurrent second-line hormonal agents, including ketoconazole, diethylstilbestrol, other estrogen-like agents, or finasteride No concurrent corticosteroids unless patient is on a stable maintenance dose of hydrocortisone (≤ 30 mg/day) for ≥ 3 months

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: Treatment (cixutumumab, temsirolimus)<br>Patients receive cixutumumab IV over 60-70 minutes and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Biological: Cixutumumab<br>* Given IV<br>* Other names: IMC-A12;Other: Diagnostic Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Temsirolimus<br>* Given IV<br>* Other names: Torisel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cTTP | Defined as the time from the first day of treatment to the earliest one of the following: tumor progression by RECIST; unequivocal evidence of progression by bone scan (at least two new lesions with confirmation at subsequent imaging); new skeletal events; symptomatic progression; or other clinical events attributable to prostate cancer that necessitate major interventions. This Outcome Measure is related to the Phase II portion of the Trial, which did not occur. Therefore, there is no data to report. | Up to 4 weeks after completion of study treatment | 
| Tumor Response Rate | Defined by modified Response Evaluation Criteria in Solid Tumors (RECIST) and/or the proportion of patients who achieve a greater than 50% reduction in serum PSA compared to baseline. | Up to 4 weeks after completion of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PSA Doubling Time | Compared using descriptive statistics. PSA doubling time is defined as the number of months it would take for PSA to increase two-fold. PSADT is inversely proportional to the slope of the regression line for the relation between log PSA and time. If this slope is negative, so the patient's PSA is going down over time, then the PSADT is negative. | Week 1, Week 5, Week 9, Week 13, Week 17, Week 21 and Week 25 | 
| Duration of Effect | Summarized using descriptive statistics. | From the time of first dose until the time of progression, assessed up to 4 weeks after completion of study treatment | 
| Maximal Percentage Change in Serum PSA as Compared to Week 12 Versus Baseline | Summarized using descriptive statistics (eg, mean, standard deviation, median, minimum, maximum). Maximum percent change in serum PSA (i.e., 100%*[(value at Week 12 minus value at baseline)/value at baseline]) | From baseline to week 12 | 
| Progression-free Survival | Summarized using descriptive statistics. Median PFS over time will be determined using Kaplan Meier method. This Outcome Measure was related to the Phase 2 portion of the study, which did not occur. Therefore, there is no data to report. | From the time of first dose until objective tumor progression or death, assessed up to 4 weeks after completion of study treatment | 
| Rate of Adverse Events According to NCI CTCAE Version 4.0 | Adverse event summaries will be organized by body system, frequency of occurrence, intensity (ie, severity grade), and causality or attribution. Please see Adverse Event/Serious Adverse Event Section. | Up to 4 weeks after completion of study treatment |