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

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies how well linsitinib works in treating patients with asymptomatic or mild symptomatic metastatic prostate cancer. Linsitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
-----------------
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.

Official Title
-----------------
A Phase 2 Study of OSI-906 in Patients With Asymptomatic or Mildly Symptomatic (Non-Opioid Requiring) Metastatic Castrate Resistant Prostate Cancer (CRPC)

Conditions
-----------------
Adenocarcinoma of the Prostate, Hormone-resistant Prostate Cancer, Recurrent Prostate Cancer, Stage IV Prostate Cancer

Intervention / Treatment
-----------------
* Drug: linsitinib
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (linsitinib)<br>Patients receive linsitinib PO 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. | Drug: linsitinib<br>* Oral Linsitinib 150mg, twice a day, days 1- 28<br>* Other names: OSI-906;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA Response Analyzed Using the PCWG2 Definition | Number of patients with a PSA Response will be evaluated according to the recommendations from National Cancer Institute Prostate-Cancer Working Group 2 (PCWG2) criteria. PSA decline of at least 50% from baseline confirmed by a second measurement at least 4 weeks later. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Toxicities Based on CTCAE Version 4.0 Criteria | Number of patients with at least possibly related to treatment toxicities grade 3 or higher based on Common Terminology Criteria for Adverse Events. | Up to 2 years | 
| Number of Patients With Bidimensional Measurable Disease RECIST-based Response | RECIST response categories: Progressive disease (PD): >=20% increase in sum of longest diameter (LD) of target lesion(s), taking as reference smallest sum LD recorded since treatment started. Complete response (CR): disappearance of all target lesions. Partial response (PR): >=30% decrease in sum of LD of target lesion(s), taking as reference baseline sum LD. Stable disease (SD): neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD. | Up to 2 years | 
| Time to PSA Progression (TTPP) Analyzed Using the PCWG2 Definition | TTPP will be measured from protocol registration to appearance of PSA progression as defined by the criteria of the PSA Working Group response criteria. The end point for progression will be calculated at the time a 25% increase in PSA has been achieved. | assessed up to 12 weeks | 
| Overall Survival Based on the RECIST v1.1 | The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). | Up to 2 years | 
| Progression Free Survival | Progression Free survival (PFS) time was measured as the time from the date of on study up to the date of occurrence of the first event defining a disease progression or death due to any cause, whichever occurred first. | assessed up to 2 years |