Dose-finding Study in Platinum-Resistant Ovarian Cancer

NCT01653912 | Completed Phase 1 Results

• 2 other identifiers: PKB1166112012-002483-27
• Study Type: interventional
• Target: 59
• Locations: 3 countries
• Sites: 10

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.

Conditions

Recurrent Platinum-resistant Ovarian Cancer

Keywords

cancer; ovarian; platinum-resistant

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (6)

• ORR in Phase 1 Subjects With Recurrent Platinum-resistant Ovarian Cancer

  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

  Up to Day 51

• Phase 2: Response Rate (RR) Defined by Gynecologic Cancer Intergroup (GCIG) CA 125

  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)

  From first dose until disease progression or death (approximately 36 months)

Study Arms (1)

GSK2110183, carboplatin and paclitaxel

EXPERIMENTAL

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

Interventions

GSK2110183 in combination with carboplatin and paclitaxel DRUG

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.

Also known as: Taxol (paclitaxel), Paraplatin (carboplatin), AKT Inhibitor

GSK2110183, carboplatin and paclitaxel

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Accenture: lead

Study Sites (10)

Royal Brisbane and Women's Hospital

Herston, Queensland, 4029, Australia

Location

Peter MacCallum Cancer Centre

East Melbourne, Victoria, 8006, Australia

Location

Western Hospital

Footscray, Victoria, 3011, Australia

Location

Royal Women's Hospital

Parkville, Victoria, 3052, Australia

Location

Sir Charles Gairdner Hospital

Nedlands, Western Australia, 6009, Australia

Location

Medical Radiology Scientific Center of Ministry of Healthcare and Social Development of RF

Omskaya, 249036, Russia

Location

City Clinical Oncology Dispensary

Saint Petersburg, 198255, Russia

Location

Mount Vernon Cancer Center

Northwood, Middlesex, London, HA6 2RN, United Kingdom

Location

Royal Surrey County Hospital NHS Foundation Trust

Guildford, Surry, GU2 7XP, United Kingdom

Location

Imperial College Healthcare NHS Trust

London, W 12 0HS, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 30563934 DERIVED

MeSH Terms

Conditions

Neoplasms

Interventions

GSK2110183; Carboplatin; Paclitaxel

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharma AG

+41 613241111

Study Officials

• Richard A Brigandi, MD, PhD, FAAP

  GlaxoSmithKline

  STUDY DIRECTOR

• Anne L Hamilton

  Royal Women's Hospital

  PRINCIPAL INVESTIGATOR

• Sarah P Blagden

  Imperial College Healthcare NHS Trust

  PRINCIPAL INVESTIGATOR

• Linda Mileshkin

  Peter MacCallum Cancer Centre, Australia

  PRINCIPAL INVESTIGATOR

• Shirley S Wong

  Western Hospital

  PRINCIPAL INVESTIGATOR

• Andrew Dean

  Sir Charles Gairdner Hospital

  PRINCIPAL INVESTIGATOR

• Marcia Hall

  Mount Vernon Cancer Center

  PRINCIPAL INVESTIGATOR

• Bhawana Awasthy, MD

  Syneos Health

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 27, 2012
• First Posted: July 31, 2012
• Study Start: November 1, 2012
• Primary Completion: July 1, 2015
• Study Completion: November 1, 2015
• Last Updated: April 2, 2018
• Results First Posted: April 2, 2018

Record last verified: 2017-08

Locations

AU (5); RU (2); GB (3)