Linsitinib in Treating Patients With Asymptomatic or Mildly Symptomatic Metastatic Prostate Cancer

PRIMARY OBJECTIVES:

I. To evaluate time to prostate-specific antigen (PSA) progression based on Prostate Cancer Working Group (PCWG2) criteria.

II. To evaluate PSA response (proportion of patients achieving a PSA decline > 50% according to PCWG2 criteria in patients receiving linsitinib [OSI-906]).

III. To evaluate overall response rate (ORR) in patients with Response Evaluation Criteria in Solid Tumors (RECIST)-defined measurable disease receiving OSI-906.

SECONDARY OBJECTIVES:

I. To evaluate the effect of OSI-906 on time-to opiate use for cancer pain. II. To evaluate the effect of OSI-906 on radiographic progression-free survival (rPFS) of patients with asymptomatic or mildly symptomatic (non-opioid requiring) castrate-resistant prostate cancer (CRPC).

III. To evaluate the overall survival (OS) of patients with asymptomatic or mildly symptomatic (non-opioid requiring) CRPC receiving OSI-906.

IV. To further evaluate the safety of OSI-906 in patients with asymptomatic or mildly symptomatic (non-opioid requiring) CRPC.

TERTIARY OBJECTIVES:

I. To describe the effects of OSI-906 in the levels of androstenedione, dehydroepiandrostenedione (DHEA), DHEA-sulfate, p insulin-like growth factor-1 receptor (IGF-IR), and p-insulin receptor (IR). (Exploratory) II. To describe the effects of OSI-906 in the levels of transforming growth factor (TGF)-beta (b1), interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha (a), and monocyte chemotactic protein 1 (MCP-1) as markers of metastatic progression. (Exploratory) III. To describe the effects of OSI-906 on the number of circulating tumor cells (CTCs) and endothelial cells (CECs). (Exploratory) IV. To use ribonucleic acid (RNA) extracted from CTCs to evaluate effects on downstream targets of IGF-1R signaling after OSI-906 treatment. (Exploratory) V. To measure the effect of OSI-906 on the expression of IGF-1R on CTCs. (Exploratory)

OUTLINE:

Patients receive linsitinib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo serum and plasma sample collection at baseline, on day 1 of courses 2 and 4, and after completion of study treatment for correlative studies.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

Inclusion criteria

• Histologically confirmed adenocarcinoma of the prostate
• Surgically or medically castrated, with testosterone levels of < 50 ng/dL (< 2.0 nM); if the patient is being treated with luteinizing hormone-releasing hormone (LHRH) agonists (patient who has not undergone orchiectomy), this therapy must have been initiated at least 4 weeks prior to course 1 Day 1 and must be continued throughout the study
• Metastatic disease documented by positive bone scan or metastatic lesions other than liver or visceral metastasis on computed tomography (CT) or magnetic resonance imaging (MRI); if lymph node metastasis is the only evidence of metastasis, it must be ≥ 2 cm in diameter
• Prostate cancer progression documented by PSA according to PCWG2 or radiographic progression according to modified RECIST criteria
• Asymptomatic or mildly symptomatic from prostate cancer; a score of 0-1 on Brief Pain Inventory (BPI)-Short Form (SF) Question #3 (worst pain in last 24 hours) will be considered asymptomatic, and a score of 2-3 will be considered mildly symptomatic
• Patients who received combined androgen blockade or received second-line anti-androgen in the context of CRPC must have shown PSA progression after discontinuing the anti-androgen prior to enrollment (≥ 4 weeks since last flutamide, ≥ 6 weeks since last bicalutamide or nilutamide) and have progressive disease
• No patients with known brain metastases
• Understand and voluntarily sign an informed consent form
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Hemoglobin ≥ 10.0 g/dL independent of transfusion
• Absolute neutrophil count ≥ 1,500/mcL
• Platelet count ≥ 100,000/μL
• Serum albumin ≥ 3.5 g/dL
• Serum creatinine < 1.5 times upper limit of normal (ULN) OR a calculated creatinine clearance ≥ 60 mL/min
• Serum potassium ≥ 3.5 mmol/L
• Serum bilirubin < 1.5 times ULN (except for patients with documented Gilbert's disease)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 times ULN
• Able to swallow the study drug
• Life expectancy of at least 6 months
• Men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation
• No history of clinically significant heart disease as evidenced by myocardial infarction or arterial thrombotic events in the past 6 months, severe or unstable angina, New York Heart Association (NYHA) Class II-IV heart disease, or cardiac ejection fraction measurement of < 50% at baseline
• No prolonged QTc > 470 msec (mean QTc with Bazett's correction) or history of familial long QT syndrome
• No other malignancy, except non-melanoma skin cancer, with a ≥ 30% probability of recurrence within 24 months
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to OSI-906
• No uncontrolled intercurrent illness including, but not limited to, psychiatric illness/social situations that would limit compliance with study requirements
• Patients with insulin-dependent diabetes are excluded
• Patients with known history of HIV on combination antiretroviral therapy are ineligible
• Patients with known infectious hepatitis A, B, or C are ineligible
• No condition that, in the opinion of the investigator, would preclude participation in this trial
• See Disease Characteristics
• Prior therapy with ketoconazole and steroids is allowed provided patients have been off treatment for 4 weeks
• Prior investigational agents with novel adrenal inhibitors (i.e., Abiraterone or TAK700) are allowed provided these agents have been discontinued at least 4 weeks prior to enrollment
• Prior investigational agents with novel antiandrogens (i.e., MDV 3100) are allowed provided these agents have been discontinued at least 6 weeks prior to enrollment
• Prior therapy with Sipuleucel-T is allowed provided patients have documented evidence of disease progression as stated above
• Patients receiving any other hormonal therapy, including any dose of Megestrol acetate (Megace), Proscar (finasteride), any herbal product known to decrease PSA levels (e.g., Saw Palmetto and PC-SPES), or any systemic corticosteroid must discontinue the agent for at least 4 weeks prior to enrollment; progressive disease (as defined above) must be documented after discontinuation of the hormonal therapy
• Patients on stable doses of bisphosphonates that show subsequent tumor progression may continue on this medication at the discretion of the treating physician; however, patients are not allowed to initiate bisphosphonate therapy within 4 weeks prior to starting therapy or throughout the study
• No prior systemic chemotherapy for CRPC; prior neoadjuvant and adjuvant chemotherapy are allowed when completed at least 12 months prior to enrollment
• No use of opiate analgesics for cancer-related pain, including codeine and dextropropoxyphene, currently or anytime within 4 weeks of Cycle 1 Day 1
• No prior use of IGF-1R inhibitors (monoclonal antibody or small molecule)
• No palliative radiation therapy to bone metastasis or radionuclide therapy for treatment of metastatic CRPC within 4 weeks of Cycle 1 Day 1
• Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine are prohibited

• Other less potent CYP1A2 inhibitors/inducers are not excluded
• Supplements or complementary medicine/botanicals are not permitted while on protocol therapy, except for any combination of the following:

• Conventional multivitamin supplements
• Selenium
• Lycopene
• Soy supplements
• The use of concomitant steroids is not allowed unless patients are receiving physiological replacement disease for documented adrenal insufficiency
• Use of drugs that have a known risk of causing Torsades de Pointes (TdP) are prohibited within 14 days prior to study enrollment