Dose-finding Study in Platinum-Resistant Ovarian Cancer

Study Overview
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Brief Summary
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Dose-finding study of GSK2110183 administered in combination with carboplatin and paclitaxel to any subject with recurrent ovarian cancer. Safety and efficacy study of GSK2110183 administered in combination with carboplatin and paclitaxel to subjects with platinum-resistant ovarian cancer.

Detailed Description
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PKB116611 is an open-label Phase I/II study of the investigational drug GSK2110183 given in combination with carboplatin and paclitaxel to subjects with recurrent ovarian cancer. Phase I is a dose escalation evaluation of daily oral doses of GSK2110183 administered in combination with every 3 week carboplatin and paclitaxel to any subject with recurrent ovarian cancer. Phase II is a single arm evaluation of the clinical efficacy of the combination identified in Phase I to subjects with platinum-resistant ovarian cancer.

Official Title
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An Open-Label Phase I/II Study of GSK2110183 in Combination With Carboplatin and Paclitaxel in Subjects With Platinum-Resistant Ovarian Cancer

Conditions
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Recurrent Platinum-resistant Ovarian Cancer

Intervention / Treatment
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* Drug: GSK2110183 in combination with carboplatin and paclitaxel


Participation Criteria
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Eligibility Criteria
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Phase I Inclusion Criteria: Female, 18 years of age as of signing the informed consent form, capable of giving/complying with written informed consent Histologically or cytologically confirmed serous ovarian cancer (includes primary peritoneal and Fallopian tube) Negative serum pregnancy test in women of childbearing potential within 14 days of first dose of treatment, agree to use effective contraception during/after (6 months post dose of paclitaxel or 30 days post dose GSK2110183 whichever is longer) Performance Status score of 0-2 according to the ECOG scale. Able to swallow and retain oral medication Subjects diagnosed previously with Type 2 diabetes must have been diagnosed ≥ 6 months prior to enrollment Prior treatment-related toxicities (except for alopecia) must be ≤ Grade 1 according to NCI-CTCAE (Version 4.0 [NCI, 2009]) at the time of treatment allocation OR ≤ Grade 2 and stable for 4 weeks or longer at the time of screening evaluation. Exception: Subjects with peripheral neuropathy >/= Grade 2 will NOT be eligible Adequate organ system function Phase II Inclusion Criteria: Cohort A Phase I criteria Documented complete or partial response by RECIST to at least 1 prior platinum-based therapy Progression defined by either (1) RECIST v1.1 criteria or (2) GCIG CA 125 criteria associated with symptoms necessitating treatment between 1 and 6 months of prior platinum-based therapy either in adjuvant or metastatic setting Subjects allowed to have a maximum of one non-platinum-based therapy between the onset of platinum resistance Must have radiologically measurable disease i.e. presenting with at least one measurable lesion per RECIST 1.1 Cohort B Phase I criteria Documented complete or partial response by RECIST to at least 1 prior platinum-based therapy Progression defined by either (1) RECIST v1.1 criteria or (2) GCIG CA 125 criteria associated with symptoms necessitating treatment while being treated with a regimen containing carboplatin and paclitaxel (or within 4 weeks of completing treatment) Subjects will be required to start on treatment within 8 weeks after the last infusion of chemotherapy and may not have had any other anti-cancer therapy in the intervening time Must have radiologically measurable disease i.e. presenting with at least one measurable lesion per RECIST 1.1 Additional restrictions on number of prior therapies may be added to eligibility criteria based on emerging data Exclusion Criteria: History of another malignancy (some exceptions may apply) Serious and/or unstable pre-existing medical or psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures Current use of prohibited medication during treatment. Chemotherapy, immunotherapy, or other anti-cancer therapy within 14 days prior to the first dose study drug Radiotherapy prior to initiation of therapy (some exceptions may apply) Contraindications (identified by the investigator) to the doses of carboplatin and/or paclitaxel History of reduction in standard of care paclitaxel dose for peripheral neuropathy No known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs similar or related to GSK2110183 No known delayed hypersensitivity reaction or idiosyncratic reaction to drugs similar to carboplatin or paclitaxel (some exceptions may apply) Prior use of a drug that targets AKT including perifosine History of Type 1 diabetes Gastrointestinal disease or other condition that could affect absorption or predispose subject to gastrointestinal ulceration Mucosal or internal bleeding Major surgery within the last four weeks Infection requiring parenteral or oral anti-infective treatment Severe or uncontrolled systemic diseases Brain metastases and/or leptomeningeal disease QTcF interval ≥ 470 msecs Bundle branch block, pacemaker or clinically significant ECG abnormalities including 2nd degree (Type II) or 3rd degree atrioventricular (AV) block History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty,stenting or bypass grafting within six months of Screening Class II, III or IV heart failure as defined by the NYHA functional classification system Pregnant or lactating female Malignancies related to HIV or solid organ transplant; history of known HIV, history of know HBV surface antigen positivity (subjects with documented laboratory evidence of HBV clearance may be enrolled) or positive HCV antibody

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: GSK2110183, carboplatin and paclitaxel<br>Subjects will be treated with a maximum of six doses of carboplatin + paclitaxel in combination with continuous daily GSK2110183 followed by single agent GSK2110183 at the single-agent MTD of 125 mg or above oral daily. | Drug: GSK2110183 in combination with carboplatin and paclitaxel<br>* Phase I is a dose escalation evaluation of increasing doses of GSK2110183 administered on a continuous daily schedule in combination with carboplatin AUC 5 and paclitaxel 175mg/m2 given every three weeks for a maximum 6 cycles. The dosing regimen identified in Phase I will then be evaluated in Phase II, a single arm study focused on clinical efficacy. Treatment with the three drug regimen will continue for a maximum of 6 x 21 day cycles followed by continuous GSK2110183 at the single agent MTD. Subjects may continue on study drug until progression, death or unacceptable toxicity.<br>* Other names: AKT Inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade Greater Than or Equal to (≥) 3 in Severity |  | Up to Week 3 | 
| Phase 1 Safety: Number of Subjects Reporting Adverse Events | Study Treatment refers to GSK2110183 with or without Carboplatin and/or Paclitaxel. Dose limiting toxicity (DLT): An event is considered a DLT if it had a reasonable causal relationship to study drug & occurs within first 3 weeks of therapy & met at least one of the following criteria: Grade 3 or 4 non-hematologic toxicity as described in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.0, 2009 [NCI, 2009] with the exceptions of Grade 3 electrolyte disturbances that respond to correction within 24 hours; or Grade 3 rash, diarrhea, nausea, vomiting and mucositis that responded to standard medical supportive care within 48 hours). Grade 4 neutropenia lasting ≥5 days Febrile neutropenia Grade 3 thrombocytopenia with bleeding Grade 4 thrombocytopenia Grade 4 anemia Treatment delay of >14 days due to unresolved toxicity Alanine aminotransferase (ALT) >3 times upper limit of normal (ULN) with bilirubin >2 times ULN | Up to Week 3 | 
| Phase 1: Maximum Tolerated Dose (MTD) of GSK2110183 | MTD is defined as the highest dose at which 1 or fewer of up to 6 subjects experience a dose limiting toxicity (DLT) during the first 3 weeks of combination therapy. MTD was considered exceeded if 2 or more subjects in a cohort of up to 6 subjects experienced a DLT. | Up to Week 3 | 
| Overall Response Rate (ORR) in Phase 2 Subjects With Recurrent Platinum-resistant Ovarian Cancer (Cohort A) | Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST) 1.1 criteria for target lesions and assessed by MRI: Complete Response (CR) is Disappearance of all target lesions and Partial Response (PR) is greater than or equal to (≥) 30% decrease in the sum of the longest diameter of target lesions. Overall Response (OR) = CR + PR. | Every 3 weeks up to 6 months | 
| ORR in Phase 2 Subjects With Recurrent Platinum-refractory Ovarian Cancer (Cohort B) | Per RECIST version 1.1 criteria for target lesions and assessed by MRI: Complete Response (CR) is Disappearance of all target lesions and Partial Response (PR) is ≥30% decrease in the sum of the longest diameter of target lesions. Overall Response (OR) = CR + PR. | Every 3 weeks up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR in Phase 1 Subjects With Recurrent Platinum-resistant Ovarian Cancer | Per RECIST version 1.1 criteria for target lesions and assessed by MRI: Complete Response (CR) is disappearance of all target lesions and Partial Response (PR) is ≥30% decrease in the sum of the longest diameter of target lesions. Overall Response (OR) = CR + PR. | Up to Week 3 | 
| Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade ≥3 in Severity |  | Up to Day 21 (Phase 2) | 
| Phase 2 Safety: Number of Subjects Reporting Adverse Events | Dose limiting toxicity (DLT): An event is considered a DLT if it had a reasonable causal relationship to study drug & occurs within first 3 weeks of therapy & met at least one of the following criteria: Grade 3 or 4 non-hematologic toxicity as described in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.0, 2009 [NCI, 2009] with the exceptions of Grade 3 electrolyte disturbances that respond to correction within 24 hours; or Grade 3 rash, diarrhea, nausea, vomiting and mucositis that responded to standard medical supportive care within 48 hours). Grade 4 neutropenia lasting ≥5 days Febrile neutropenia Grade 3 thrombocytopenia with bleeding Grade 4 thrombocytopenia Grade 4 anemia Treatment delay of >14 days due to unresolved toxicity Alanine aminotransferase (ALT) >3 times upper limit of normal (ULN) with bilirubin >2 times ULN | Up to Day 51 | 
| Phase 2: Response Rate (RR) Defined by Gynecologic Cancer Intergroup (GCIG) CA 125 | RR is defined by the percentage of subjects with investigator-assessed Partial Cancer Antigen (CA) 125 Response (PR) or Complete CA 125 Response (CR) at any time during the study by GCIG CA 125. PR is greater than (>) 50% decrease in CA-125 values from baseline and no clinical or radiological evidence of new lesions. CR is decrease in the CA-125 to within the normal limits and less than (<) 40 IU/mL and no clinical or radiological evidence of disease. | From Month 1 to 6 | 
| Progression Free Survival (PFS) by RECIST or Clinical Symptomatic Progression of Subjects With Recurrent Platinum-resistant Ovarian Cancer (Phase 2-Cohort A) | PFS was defined as the number of months between date of first GSK2110183 treatment and the earliest date of disease progression by RECIST or clinical symptomatic progression or death due to any cause whichever is earlier. Progression is defined using RECIST version 1.1 as at least a 20% increase in the sum of the longest diameter of target lesion in reference to the smallest sum of the longest diameter recorded since the treatment started. | From first dose until disease progression or death (approximately 36 months) | 
| PFS by RECIST of Subjects With Recurrent Platinum-resistant Ovarian Cancer (Phase 2-Cohort A) | PFS was defined as the number of months between date of first GSK2110183 treatment and the earliest date of disease progression by RECIST or death due to any cause whichever is earlier. Progression is defined using RECIST version 1.1 as at least a 20% increase in the sum of the longest diameter of target lesion in reference to the smallest sum of the longest diameter recorded since the treatment started. | From first dose until disease progression or death (approximately 36 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer, ovarian, platinum-resistant