A Study Evaluating Intermittent and Continuous OSI-906 and Weekly Paclitaxel in Patients With Recurrent Epithelial Ovarian Cancer (and Other Solid Tumors)

Study Overview
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Brief Summary
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This is a multi-center, randomized, open-label, phase 1/2 study of continuous weekly paclitaxel and escalating doses of intermittent or continuous OSI-906 in patients with recurrent/relapsed ovarian and other solid tumors.

Detailed Description
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The phase 1 dose escalation portion will establish the maximum tolerated dose (MTD) in patients with advanced solid tumors. Once the recommended phase 2 dose (RP2D) is established for both schedules, the phase 2 study will begin. Patients with relapsed/recurrent epithelial ovarian cancer will be randomized 1:1:1 to 3 treatment groups.

Official Title
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A Phase 1/2 Study Evaluating Intermittent and Continuous OSI-906 and Weekly Paclitaxel in Patients With Recurrent Epithelial Ovarian Cancer (and Other Solid Tumors)

Conditions
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Ovarian Cancer, Solid Tumors

Intervention / Treatment
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* Drug: OSI-906
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed epithelial ovarian carcinoma Patients with fallopian or peritoneal cancer will also be eligible Patients with any solid tumor that may be treated with weekly paclitaxel will be eligible for the phase 1 portion For the phase 2 portion, patients must have elevated CA125 levels evaluable/assessable according to Gynecological Cancer Intergroup (GCIG) criteria (ie, > 70 U/mL) documented by 2 measurements at least 1 week apart Patients must have radiologically confirmed progressive disease by RECIST v1.1 criteria within 6 months prior to randomization. (patients must have measurable disease according to RECIST v1.1) Eastern Cooperative Oncology Group (ECOG) performance status(PS) 0 -1 Predicted life expectancy ≥ 12 weeks Patients may have had prior therapy, providing the following conditions are met: Chemotherapy: Prior chemotherapy must have been completed at least 3 weeks prior to study enrollment (6 weeks for mitomycin C, nitrosoureas or high-dose carboplatin [≥ 600 mg/m²]and 4 weeks for investigational drugs Patient should have recovered from any drug-related toxicities (with the exception of grade 1 neuropathy and or alopecia) Phase 1: While there is no limit on the number of prior regimens for patients entered into the phase 1 portion, any prior taxane therapy must have been administered on a 3 week schedule Phase 2: Patients must have received prior chemotherapy, which must have contained a platinum and a taxanes at some point. Any prior taxanes therapy must have been administered on a 3 week schedule. A maximum of 2 prior chemotherapy regimens are permitted. Patients must be refractory radiologically confirmed by computerized tomography (CT) scan progressive disease (PD) during chemotherapy) or resistant (radiologically confirmed by CT scan PD within six months of completing chemotherapy) to their last platinum-containing chemotherapy regimen Radiation: Patients may have had prior radiation therapy provided they have recovered from the acute, toxic effects of radiotherapy prior to registration/randomization. Radiated lesions cannot be chosen as the target lesions a. A minimum of 21 days must have elapsed between the end of radiotherapy and registration/randomization into the study unless the radiation affected less than 25% of bone marrow Surgery: Previous surgery is permitted provided that adequate wound healing has occurred prior to registration/randomization Fasting glucose ≤ 150 mg/dL (8.3 mmol/L) Adequate hematopoietic, hepatic, and renal function defined as follows: Neutrophil count ≥ 1.5 x 10 ^9 /L and platelet count > = 100 x 10^9/L; Bilirubin ≤ 1.5 x Upper Limit of Normal (ULN); AST and/or ALT ≤ 2.5 x ULN or < = 5 x ULN if patient has documented liver metastases; and Serum creatinine ≤ 1.5 x ULN Female patient must be either: Of non childbearing potential: post-menopausal (defined as at least 1 year without any menses) prior to Screening, or documented surgically sterile or status post hysterectomy (at least 1 month prior to Screening) Or, if of childbearing potential: must have a negative urine pregnancy test at Screening, and must use two forms of birth control (one of which must be a barrier method) starting at Screening and throughout the study period and for 28 days [or 5 half lives, whichever is longer] after final study drug administration Female patient must not be breastfeeding at Screening or during the study period and for 28 days [or 5 half lives of the study drug whichever is longer] after final study drug administration Female patient must not donate ova starting at Screening and throughout the study period and for 28 days [or 5 half lives of the study drug whichever is longer] after final study drug administration Patients must provide verbal and written informed consent to participate in the study Exclusion Criteria: Diabetes mellitus currently requiring medication (eg, insulin or oral hypoglycemics) During the phase 2 portion, patients with histology of abdominal adenocarcinoma of unknown origin or a diagnosis of a borderline ovarian tumor Previous or concurrent malignancies (excluding curatively treated basal or squamous cell carcinoma of the skin or cervical carcinoma in situ) unless the patient has been in remission for at least 3 years History of significant cardiovascular disease unless the disease is well-controlled. Significant cardiac diseases includes second/third degree heart block; significant ischemic heart disease; poorly controlled hypertension; congestive heart failure of New York Heart Association (NYHA) Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea) History of cerebrovascular accident (CVA) within 6 months prior to registration/randomization or that is not stable Prior therapy with an insulin-like growth factor (IGF-1R) inhibitor Use of drugs that have a risk of causing QT interval prolongation within 14 days prior to Day 1 dosing Known or prior hypersensitivity to taxanes in spite of premedication or drugs containing Cremophor Gastro-intestinal abnormalities, including bowel obstruction, inability to take oral medication, requirement for intravenous (IV) alimentation,active peptic ulcer or prior surgical procedures or bowel resection affecting absorption Active infection or serious underlying medical condition (including any type of active seizure disorder within 12 months prior to registration/randomization) that would impair the ability of the patient to receive protocol treatment History of any psychiatric condition that might impair the patient's ability to understand or to comply with the requirements of the study or to provide informed consent Pregnancy or breast-feeding Symptomatic brain metastases that are not stable, require steroids, are potentially life threatening, or that have required radiation within 28 days prior to registration/randomization History of allergic reactions attributed to compounds of similar chemical or biologic composition to the study drug History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is symptomatic or requires treatment (≥ grade 3), left bundle branch block (LBBB), or asymptomatic sustained ventricular tachycardia are not allowed. Patients with atrial fibrillation controlled by medication are not excluded. Patients with mean QTcF interval ≥ 450 msec at screening are excluded Use of drugs that have a known risk of causing Torsade de Pointes (TdP) or that that have a risk of causing QT interval prolongation within 14 days prior to Day 1 dosing are prohibited Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine. Other less potent CYP1A2 inhibitors/inducers are not excluded Participated in any interventional clinical study or has been treated with any investigational drugs within 30 days or 5 half lives whichever is longer, prior to the initiation of Screening or during the course of the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Arm A<br>Intermittent OSI-906 Once Daily (QD) on Days 1 - 3, 8 - 10, and 15 - 17 with paclitaxel on Days 1, 8, and 15 (except Treatment Period 1 (TP 1); in TP 1 OSI-906 on Days 1 - 3, 8 - 10, 15 - 17, and 22 - 24 with paclitaxel on Days 8, 15, and 22) | Drug: OSI-906<br>* Administered orally<br>Drug: Paclitaxel<br>* Administered intravenously<br>|
| Experimental: Phase 1 Arm B1<br>Continuous OSI-906 Twice Daily (BID) (Days 1 - 21) with paclitaxel dosing on Days 1, 8, and 15;(except TP 1; in TP 1 OSI-906 on Days 1 - 3, 8 - 10, 15 - 17, and 22 - 24 with paclitaxel on Days 8, 15 and 22) | Drug: OSI-906<br>* Administered orally<br>Drug: Paclitaxel<br>* Administered intravenously<br>|
| Experimental: Phase 1 Arm B2<br>Continuous OSI-906 BID (Days 1 - 21) with paclitaxel dosing on Days 1, 8, and 15 (except TP 1; in TP 1 OSI-906 on Days 1 - 3, 8 - 10, 5 - 17, and 22 - 24 with paclitaxel on Days 8, 15, and 22); (additional PK sampling on Days 9 or 13 0r 14 for TP 1) | Drug: OSI-906<br>* Administered orally<br>Drug: Paclitaxel<br>* Administered intravenously<br>|
| Experimental: Phase 1 Arm B3<br>Continuous OSI-906 BID (Days 1 - 21) with paclitaxel dosing on Days 1, 8, and 15 with no separation in OSI-906 and paclitaxel dosing (except TP 1; in TP 1 continuous OSI-906 dosing 2 hours prior to the initiation of paclitaxel infusion on Day 8 only, with paclitaxel on Days 8, 15, and 22, and additional PK sampling on Day 9 or 13 or 14) | Drug: OSI-906<br>* Administered orally<br>Drug: Paclitaxel<br>* Administered intravenously<br>|
| Experimental: Phase 2 Arm A<br>Intermittent OSI-906 QD on Days 1 - 3, 8 - 10, and 15 - 17 with paclitaxel on Days 1, 8, and 15 | Drug: OSI-906<br>* Administered orally<br>Drug: Paclitaxel<br>* Administered intravenously<br>|
| Experimental: Phase 2 Arm B<br>Continuous OSI-906 BID from Day 1 onwards with paclitaxel on Days 1, 8, and 15 | Drug: OSI-906<br>* Administered orally<br>Drug: Paclitaxel<br>* Administered intravenously<br>|
| Experimental: Phase 2 Arm C<br>Paclitaxel on Days 1, 8, and 15 | Drug: Paclitaxel<br>* Administered intravenously<br>|
| Experimental: Phase 2 Arm C Roll-over<br>Continuous OSI-906 BID from Day 1 onwards | Drug: OSI-906<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | Primary outcome measure for Phase 1 portion | 28 days | 
| Progression Free Survival (PFS) | Primary outcome measure for the Phase 2 portion; The time from the date of randomization until date of radiographic disease progression per RECIST v1.1 or until death due to any cause | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | The proportion of patients with a confirmed response of Complete Response (CR) or Partial Response (PR) per RECEIST v1.1 | 36 months | 
| Cancer Antigen 125 (CA125) Response Rate | Response Rate is defined as at least 50% reduction in serum CA-125 levels from pretreatment levels; Response rate is the proportion of patients with a CA-125 response among evaluable patients | 36 months | 
| Duration of Response (DOR) | The time from the date of the first documented radiographic response (CR/PR) to first documented radiographic progression or death due to underlying cancer | 36 months | 
| Duration of CA-125 Response (CA-125 DOR) | The time from the date of the first documented CA-125 response to the date of CA-125 progression | 36 months | 
| Overall Survival (OS) | The time from the date of randomization until the documented date of death | 36 months | 
| Safety assessed via physician exam, vital signs, clinical laboratory tests, electrocardiograms (ECG), and adverse events |  | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ovarian, IGF-1R, Paclitaxel, Ovarian Cancer, OSI-906, Solid Tumors