Clinical trial NCT01653912: Dose-finding Study in Platinum-Resistant Ovarian Cancer
Official title: An Open-Label Phase I/II Study of GSK2110183 in Combination With Carboplatin and Paclitaxel in Subjects With Platinum-Resistant Ovarian Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Recurrent Platinum-resistant Ovarian Cancer
Keywords: cancer
ovarian
platinum-resistant
Lead sponsor: Accenture
Sponsor class: INDUSTRY
First posted: 2012-07-31
Enrollment: 59
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Phase 1: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade Greater Than or Equal to (≥) 3 in Severity
timeFrame: Up to Week 3
measure: Phase 1 Safety: Number of Subjects Reporting Adverse Events
timeFrame: Up to Week 3
measure: Phase 1: Maximum Tolerated Dose (MTD) of GSK2110183
timeFrame: Up to Week 3
measure: Overall Response Rate (ORR) in Phase 2 Subjects With Recurrent Platinum-resistant Ovarian Cancer (Cohort A)
timeFrame: Every 3 weeks up to 6 months
measure: ORR in Phase 2 Subjects With Recurrent Platinum-refractory Ovarian Cancer (Cohort B)
timeFrame: Every 3 weeks up to 6 months
Secondary outcomes:
measure: ORR in Phase 1 Subjects With Recurrent Platinum-resistant Ovarian Cancer
timeFrame: Up to Week 3
measure: Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade ≥3 in Severity
timeFrame: Up to Day 21 (Phase 2)
measure: Phase 2 Safety: Number of Subjects Reporting Adverse Events
timeFrame: Up to Day 51
measure: Phase 2: Response Rate (RR) Defined by Gynecologic Cancer Intergroup (GCIG) CA 125
timeFrame: From Month 1 to 6
measure: Progression Free Survival (PFS) by RECIST or Clinical Symptomatic Progression of Subjects With Recurrent Platinum-resistant Ovarian Cancer (Phase 2-Cohort A)
timeFrame: From first dose until disease progression or death (approximately 36 months)
measure: PFS by RECIST of Subjects With Recurrent Platinum-resistant Ovarian Cancer (Phase 2-Cohort A)
timeFrame: From first dose until disease progression or death (approximately 36 months)
Other outcomes:
Locations:
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Footscray
country: Australia
facility: Western Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Women's Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Omskaya
country: Russian Federation
facility: Medical Radiology Scientific Center of Ministry of Healthcare and Social Development of RF
city: Saint-Petersburg
country: Russian Federation
facility: City Clinical Oncology Dispensary
city: Northwood, Middlesex
country: United Kingdom
facility: Mount Vernon Cancer Center
state: London
city: Guildford
country: United Kingdom
facility: Royal Surrey County Hospital NHS Foundation Trust
state: Surry
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
Study officials:
affiliation: GlaxoSmithKline
name: Richard A Brigandi, MD, PhD, FAAP
role: STUDY_DIRECTOR
affiliation: Royal Women's Hospital
name: Anne L Hamilton
role: PRINCIPAL_INVESTIGATOR
affiliation: Imperial College Healthcare NHS Trust
name: Sarah P Blagden
role: PRINCIPAL_INVESTIGATOR
affiliation: Peter MacCallum Cancer Centre, Australia
name: Linda Mileshkin
role: PRINCIPAL_INVESTIGATOR
affiliation: Western Hospital
name: Shirley S Wong
role: PRINCIPAL_INVESTIGATOR
affiliation: Sir Charles Gairdner Hospital
name: Andrew Dean
role: PRINCIPAL_INVESTIGATOR
affiliation: Mount Vernon Cancer Center
name: Marcia Hall
role: PRINCIPAL_INVESTIGATOR
affiliation: Syneos Health
name: Bhawana Awasthy, MD
role: STUDY_DIRECTOR
References:
citation: Blagden SP, Hamilton AL, Mileshkin L, Wong S, Michael A, Hall M, Goh JC, Lisyanskaya AS, DeSilvio M, Frangou E, Stronach EA, Gopalakrishna P, Meniawy TM, Gabra H. Phase IB Dose Escalation and Expansion Study of AKT Inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-resistant Ovarian Cancer. Clin Cancer Res. 2019 Mar 1;25(5):1472-1478. doi: 10.1158/1078-0432.CCR-18-2277. Epub 2018 Dec 18.