Study of Paclitaxel, Carboplatin, and PF-05212384 in Advanced or Metastatic NSCLC (UF-STO-LUNG-002)

Study Overview
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Brief Summary
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The purpose of this research study is to determine if the study drug, Gedatolisib (PF-05212384), given in combination with paclitaxel and carboplatin will work against unresectable non-small cell lung cancer.

Detailed Description
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Approximately 70% of patients with unresectable non-small cell lung cancer (NSCLC) who receive and progress through frontline chemotherapy will be eligible for second line treatments. Any of the agents which are available for frontline therapy can be used in the salvage setting, though only erlotinib, docetaxel, and pemetrexed (in non-squamous cell carcinoma) are FDA-approved in the salvage setting based upon their demonstrated survival benefit in randomized phase III trials. All three appear to be roughly equivalent in terms of clinical benefit, which is admittedly modest, with response rates <10%, clinical benefit rates of approximately 50%, and overall survivals of approximately 6 months. Still, a substantial number of patients may not benefit from the agents in the salvage treatment setting, thus it is critical to identify those patients who stand to benefit the most. The study will consist of two phases, Ib and II. The phase Ib portion will study dose escalations in separate 3+3 cohorts using escalating doses of PF-05212384. The phase II portion will consist of a two stage Simon design. The doses for paclitaxel (200 mg/m2, Q21 days) and carboplatin (AUC=6, Q21 days) do not adjust as part of the study design. The dose of PF-05212384 will be determined during the Phase Ib portion. The primary endpoint of the phase Ib portion of this protocol is to determine a tolerable phase II dose of PF-05212384 in combination with paclitaxel and carboplatin. The primary endpoint of the phase II portion of this study is to determine the objective response rate of disease to the administration of PF-05212384 in combination with paclitaxel and carboplatin. A secondary endpoint of this study will be progression-free survival following PF-05212384 therapy.

Official Title
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A Non-Randomized Phase Ib-II Protocol of Paclitaxel, Carboplatin and the Dual PI3K/mTOR Kinase Inhibitor, PF-05212384, for Patients With Advanced, or Metastatic Non-Small Cell Carcinoma of the Lung

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Gedatolisib
* Drug: Paclitaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Institutional Review Board (IRB)-approved informed consent prior to any study-related procedures Age of 18 years or older Advanced-stage unresectable NSCLC, as confirmed by pathological and/or radiological analysis (subjects will be classified as having advanced disease if they were not eligible for, or had disease progression after, surgical or locoregional therapies) Prior chemotherapy will be allowed for other invasive malignancies, provided therapy was completed at least five years before the start of protocol therapy, and participants have recovered from all toxicities of that prior therapy Participants may have received prior chemotherapy for NSCLC In the Phase II portion, subjects must have disease which lacks PTEN expression by immunohistochemistry, or has known prior activating PI3K or inactivating PTEN gene mutations (mutations will not be assayed for specifically) Eastern Cooperative Oncology Group (ECOG) performance status score < 2 Life expectancy ≥ 12 week Participants must have measureable disease by RECIST criteria Absolute neutrophil count > 1500 mm3 (individuals with benign ethnic neutropenia may be enrolled if they have no evidence of infectious diathesis, or febrile neutropenia at the time of enrollment) Platelet count ≥ 100×109 L Hgb ≥ 8.5 g/dL (subjects may receive transfusions to achieve this, in the absence of overt bleeding) Total Bilirubin ≤ 2 mg/dL aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤ 3 times the upper limit of normal range Serum creatinine ≤1.5 times the upper limit of the normal range Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for at least 6 months after the last dose of study drug to minimize the risk of pregnancy. Prior to study enrollment, women of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. WOCBP include any woman who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is defined as: Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or For women with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL. Males with female partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 6 months following the last dose of study drug Exclusion Criteria: Uncontrolled cardiac disease, congestive heart failure, angina, arrhythmias or hypertension. Myocardial infarction or unstable angina within 2 months of treatment. Known human immunodeficiency virus (HIV) infection or chronic active Hepatitis B (subjects will not be screened for this). Active clinically serious infection > CTCAE Grade 2. Thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months. Pulmonary hemorrhage/bleeding event ≥ CTCAE Grade 2 within 4 weeks of first dose of study drug. Any other hemorrhage/bleeding event ≥ CTCAE Grade 3 within 4 weeks of first dose of study drug. Serious non-healing wound, ulcer, or bone fracture. Evidence or history of bleeding diathesis or coagulopathy Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug Women or men of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 6 months after the last dose of study drug Women who are pregnant or breastfeeding. History of any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy or that might affect the interpretation of the results of the study or that puts the subject at high risk for treatment complications, in the opinion of the treating physician. Prisoners or subjects who are involuntarily incarcerated. Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness. Subjects demonstrating an inability to comply with the study and/or follow-up procedures.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm (Phase 1b; Gedatolisib Dose Level 1[110 mg])<br> | Drug: Gedatolisib<br>* During the first phase, subjects will be sequentially enrolled to each increasing dose level, beginning with dose level 1 (110 mg) until the first dose limiting toxicity occurs, or safely accrued to dose level 3. PF-05212384 is intravenously infused over a thirty minute period. The dose given in the phase 2 portion will be the MTD determined in the phase Ib portion of the study. Dose Level 1: 110 mg Dose Level 2: 150 mg Dose Level 3: 180 mg<br>* Other names: PF-05212384;Drug: Paclitaxel<br>* Given as 200 mg/m2 infusion over a three hour period at every twenty-one days; the dose will not adjust as part of the study design.<br>* Other names: NSC-673089;Drug: Carboplatin<br>* The carboplatin dose (mg) = AUC x (CrCl + 25) where AUC = 6 depending on the dose level. carboplatin is intravenously infused over a thirty minute period following paclitaxel administration; the dose will not adjust as part of the study design.<br>* Other names: NSC-241240;|
| Experimental: Treatment Arm (Phase 1b; Gedatolisib Dose Level 2[150 mg])<br> | Drug: Gedatolisib<br>* During the first phase, subjects will be sequentially enrolled to each increasing dose level, beginning with dose level 1 (110 mg) until the first dose limiting toxicity occurs, or safely accrued to dose level 3. PF-05212384 is intravenously infused over a thirty minute period. The dose given in the phase 2 portion will be the MTD determined in the phase Ib portion of the study. Dose Level 1: 110 mg Dose Level 2: 150 mg Dose Level 3: 180 mg<br>* Other names: PF-05212384;Drug: Paclitaxel<br>* Given as 200 mg/m2 infusion over a three hour period at every twenty-one days; the dose will not adjust as part of the study design.<br>* Other names: NSC-673089;Drug: Carboplatin<br>* The carboplatin dose (mg) = AUC x (CrCl + 25) where AUC = 6 depending on the dose level. carboplatin is intravenously infused over a thirty minute period following paclitaxel administration; the dose will not adjust as part of the study design.<br>* Other names: NSC-241240;|
| Experimental: Treatment Arm (Phase 1b; Gedatolisib Dose Level 3[180 mg])<br> | Drug: Gedatolisib<br>* During the first phase, subjects will be sequentially enrolled to each increasing dose level, beginning with dose level 1 (110 mg) until the first dose limiting toxicity occurs, or safely accrued to dose level 3. PF-05212384 is intravenously infused over a thirty minute period. The dose given in the phase 2 portion will be the MTD determined in the phase Ib portion of the study. Dose Level 1: 110 mg Dose Level 2: 150 mg Dose Level 3: 180 mg<br>* Other names: PF-05212384;Drug: Paclitaxel<br>* Given as 200 mg/m2 infusion over a three hour period at every twenty-one days; the dose will not adjust as part of the study design.<br>* Other names: NSC-673089;Drug: Carboplatin<br>* The carboplatin dose (mg) = AUC x (CrCl + 25) where AUC = 6 depending on the dose level. carboplatin is intravenously infused over a thirty minute period following paclitaxel administration; the dose will not adjust as part of the study design.<br>* Other names: NSC-241240;|
| Experimental: Treatment Arm (Phase 2; MTD of Gedatolisib from Phase Ib)<br> | Drug: Gedatolisib<br>* During the first phase, subjects will be sequentially enrolled to each increasing dose level, beginning with dose level 1 (110 mg) until the first dose limiting toxicity occurs, or safely accrued to dose level 3. PF-05212384 is intravenously infused over a thirty minute period. The dose given in the phase 2 portion will be the MTD determined in the phase Ib portion of the study. Dose Level 1: 110 mg Dose Level 2: 150 mg Dose Level 3: 180 mg<br>* Other names: PF-05212384;Drug: Paclitaxel<br>* Given as 200 mg/m2 infusion over a three hour period at every twenty-one days; the dose will not adjust as part of the study design.<br>* Other names: NSC-673089;Drug: Carboplatin<br>* The carboplatin dose (mg) = AUC x (CrCl + 25) where AUC = 6 depending on the dose level. carboplatin is intravenously infused over a thirty minute period following paclitaxel administration; the dose will not adjust as part of the study design.<br>* Other names: NSC-241240;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Tolerability | To identify the maximum tolerated dose of PF-05212384 in combination with paclitaxel and carboplatin in subjects with NSCLC. | 1 year | 
| Objective Response Rate (ORR) | To estimate the objective rate of response of PF-05212384 in combination with paclitaxel and carboplatin administered to subjects with unresectable or metastatic NSCLC, according to current RECIST criteria. ORR is defined as the number of participants who achieved either a partial or complete response by RECIST 1.1 criteria. By these criteria, Complete Response (CR) is defined as the disappearance of all target lesions and Partial Response (PR) is defined as a decrease of at least 30% in the sum of the longest diameter of the target lesions. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lung, carcinoma