Dose-finding Study in Platinum-Resistant Ovarian Cancer

• ClinicalTrials.gov Identifier: NCT01653912
• Recruitment Status: Completed
• First Posted: July 31, 2012
• Results First Posted: April 2, 2018
• Last Update Posted: April 2, 2018
• Sponsor: Accenture
• Information provided by (Responsible Party): Accenture

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Recurrent Platinum-resistant Ovarian Cancer	Drug: GSK2110183 in combination with carboplatin and paclitaxel	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 59 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: November 2012
• Actual Primary Completion Date: July 2015
• Actual Study Completion Date: November 2015

Arms and Interventions

Arm

Intervention/treatment

Experimental: GSK2110183, 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.

Drug: GSK2110183 in combination with carboplatin and paclitaxel; 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.; Other Names: Taxol (paclitaxel); Paraplatin (carboplatin); AKT Inhibitor

Outcome Measures

Primary Outcome Measures :

1. Phase 1: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade Greater Than or Equal to (≥) 3 in Severity [ Time Frame: Up to Week 3 ]
2. Phase 1 Safety: Number of Subjects Reporting Adverse Events [ Time Frame: 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
3. Phase 1: Maximum Tolerated Dose (MTD) of GSK2110183 [ Time Frame: 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.
4. Overall Response Rate (ORR) in Phase 2 Subjects With Recurrent Platinum-resistant Ovarian Cancer (Cohort A) [ Time Frame: 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.

5. ORR in Phase 2 Subjects With Recurrent Platinum-refractory Ovarian Cancer (Cohort B) [ Time Frame: 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 :

1. ORR in Phase 1 Subjects With Recurrent Platinum-resistant Ovarian Cancer [ Time Frame: 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.

2. Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade ≥3 in Severity [ Time Frame: Up to Day 21 (Phase 2) ]
3. Phase 2 Safety: Number of Subjects Reporting Adverse Events [ Time Frame: 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
4. Phase 2: Response Rate (RR) Defined by Gynecologic Cancer Intergroup (GCIG) CA 125 [ Time Frame: 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.
5. Progression Free Survival (PFS) by RECIST or Clinical Symptomatic Progression of Subjects With Recurrent Platinum-resistant Ovarian Cancer (Phase 2-Cohort A) [ Time Frame: 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.
6. PFS by RECIST of Subjects With Recurrent Platinum-resistant Ovarian Cancer (Phase 2-Cohort A) [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

Australia, Queensland

Royal Brisbane and Women's Hospital

Herston, Queensland, Australia, 4029

Australia, Victoria

Peter MacCallum Cancer Centre

East Melbourne, Victoria, Australia, 8006

Western Hospital

Footscray, Victoria, Australia, 3011

Royal Women's Hospital

Parkville, Victoria, Australia, 3052

Australia, Western Australia

Sir Charles Gairdner Hospital

Nedlands, Western Australia, Australia, 6009

Russian Federation

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

Omskaya, Russian Federation, 249036

City Clinical Oncology Dispensary

Saint-Petersburg, Russian Federation, 198255

United Kingdom

Mount Vernon Cancer Center

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

Royal Surrey County Hospital NHS Foundation Trust

Guildford, Surry, United Kingdom, GU2 7XP

Imperial College Healthcare NHS Trust

London, United Kingdom, W 12 0HS

Sponsors and Collaborators

Accenture

Investigators

• Study Director: Richard A Brigandi, MD, PhD, FAAP; GlaxoSmithKline
• Principal Investigator: 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
• Study Director: Bhawana Awasthy, MD; Syneos Health

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Accenture
• ClinicalTrials.gov Identifier: NCT01653912
• Other Study ID Numbers: PKB116611; 2012-002483-27 ( EudraCT Number )
• First Posted: July 31, 2012
• Results First Posted: April 2, 2018
• Last Update Posted: April 2, 2018
• Last Verified: August 2017

Keywords provided by Accenture:

cancer; ovarian; platinum-resistant

Additional relevant MeSH terms:

Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Paclitaxel; Albumin-Bound Paclitaxel; Carboplatin; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action