Dose-finding Study in Platinum-Resistant Ovarian Cancer

Phase 1

Completed

Conditions: Recurrent Platinum-resistant Ovarian Cancer

Interventions: Drug: GSK2110183 in combination with carboplatin and paclitaxel

Registration Number: NCT01653912

Lead Sponsor: Accenture

Brief Summary: * 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 59

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
GSK2110183, carboplatin and paclitaxel	GSK2110183 in combination with carboplatin and paclitaxel	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.

Primary Outcome Measures

Name	Time	Method
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	Up to Week 3	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
Phase 1: Maximum Tolerated Dose (MTD) of GSK2110183	Up to Week 3	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.
Overall Response Rate (ORR) in Phase 2 Subjects With Recurrent Platinum-resistant Ovarian Cancer (Cohort A)	Every 3 weeks up to 6 months	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.
ORR in Phase 2 Subjects With Recurrent Platinum-refractory Ovarian Cancer (Cohort B)	Every 3 weeks up to 6 months	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.

Secondary Outcome Measures

Name	Time	Method
ORR in Phase 1 Subjects With Recurrent Platinum-resistant Ovarian Cancer	Up to Week 3	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.
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	Up to Day 51	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
Phase 2: Response Rate (RR) Defined by Gynecologic Cancer Intergroup (GCIG) CA 125	From Month 1 to 6	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.
Progression Free Survival (PFS) by RECIST or Clinical Symptomatic Progression of Subjects With Recurrent Platinum-resistant Ovarian Cancer (Phase 2-Cohort A)	From first dose until disease progression or death (approximately 36 months)	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.
PFS by RECIST of Subjects With Recurrent Platinum-resistant Ovarian Cancer (Phase 2-Cohort A)	From first dose until disease progression or death (approximately 36 months)	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.

Trial Locations

Locations (10): Royal Brisbane and Women's Hospital
🇦🇺
Herston, Queensland, Australia
Imperial College Healthcare NHS Trust
🇬🇧
London, United Kingdom
Sir Charles Gairdner Hospital
🇦🇺
Nedlands, Western Australia, Australia
Medical Radiology Scientific Center of Ministry of Healthcare and Social Development of RF
🇷🇺
Omskaya, Russian Federation
Western Hospital
🇦🇺
Footscray, Victoria, Australia
City Clinical Oncology Dispensary
🇷🇺
Saint-Petersburg, Russian Federation
Peter MacCallum Cancer Centre
🇦🇺
East Melbourne, Victoria, Australia
Mount Vernon Cancer Center
🇬🇧
Northwood, Middlesex, London, United Kingdom
Royal Surrey County Hospital NHS Foundation Trust
🇬🇧
Guildford, Surry, United Kingdom
Royal Women's Hospital
🇦🇺
Parkville, Victoria, Australia