| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033130 |
| E.1.2 | Term | Ovarian cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Phase I
To determine the safety and tolerability of GSK2110183 administered in combination with carboplatin and paclitaxel in subjects with ovarian cancer--which will be used to identify the dosing regimen to be evaluated in Phase II.
Primary Phase II
To evaluate the clinical efficacy (as measured by overall response rate) of GSK2110183 administered in combination with carboplatin and paclitaxel in subjects with recurrent platinum-resistant ovarian cancer.
To evaluate the clinical efficacy (as measured by overall response rate) of GSK2110183 administered in combination with carboplatin and paclitaxel in subjects with platinum refractory ovarian cancer.
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| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of the dosing combination of GSK2110183 administered in combination with carboplatin & paclitaxel To evaluate the clinical efficacy (as measured by CA 125 responses and response criteria incorporating both CA 125 &RECIST observations) of GSK2110183 administered in combination with carboplatin & paclitaxel in subjects with recurrent platinum-resistant ovarian cancer.
To evaluate the progression free survival (PFS) of subjects with recurrent platinum-resistant ovarian cancer treated with GSK2110183 in combination with carboplatin & paclitaxel.
To evaluate the clinical efficacy (as measured by CA 125 responses & response criteria incorporating both CA 125 and RECIST observations) of GSK2110183 administered in combination with carboplatin & paclitaxel in subjects with platinum-refractory ovarian cancer.
To evaluate the PFS of subjects with platinum-refractory ovarian cancer treated with GSK2110183 in combination with carboplatin & paclitaxel
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase I – Dose Escalation
1. Female at least 18 years of age at the time of signing the informed consent form and capable of giving written informed consent, which includes willingness to comply with the requirements and restrictions listed in the consent form
2. Histologically or cytologically confirmed serous ovarian cancer (including primary peritoneal and Fallopian tube)
3. No more than 2 prior cytotoxic chemotherapeutic regimens
4. Women of childbearing potential must have a negative serum pregnancy test within 14 days of first dose of study treatment and agree to use effective contraception, during the study and for 30 days following the last dose of study treatment.
5. Performance Status score of 0-2 according to the Eastern Cooperative Oncology Group (ECOG) scale.
6. Able to swallow and retain oral medication.
7. Subjects diagnosed previously with Type 2 diabetes must have been diagnosed ≥ 6 months prior to enrollment.
8. All 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. The only exception to the Grade 2 rule is peripheral neuropathy. Subjects with peripheral neuropathy ≥ Grade 2 will NOT be eligible.
9. Adequate organ system function
Phase II
10. Subjects must have platinum-resistant disease as defined by the following:
• Documented response (complete or partial response by RECIST) to at least one prior platinum-based therapy
• Progression defined by either (1) RECIST v1.1 criteria or (2) GCIG CA 125 criteria in association with symptoms necessitating treatment -- between 1 and 6 months of prior platinum-based therapy either in the adjuvant or metastatic setting. Subjects will be required to start on treatment for this trial within 8 months after the last platinum-based therapy and may not have had any other anti-cancer therapy in that intervening time.
•Subjects are allowed to have a maximum of one non-platinum-based therapy between the onset of platinum resistance as defined above and enrolment. Maintenance therapy defined as extension of at least one component of the treatment regimen will count towards the maximum. For example, if a subject is being treated with cisplatin + pegylated
doxorubicin and continues on pegylated doxorubicin for an additional two months after cisplatin is discontinued, the single agent pegylated doxorubicin would be considered the "one non-platinum-based therapy" for the purposes of enrolment.
• Subjects must have radiologically measurable disease i.e. presenting with at least one measurable lesion per RECIST 1.1.
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| E.4 | Principal exclusion criteria |
1. History of another malignancy.
Exception: Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
2. Any serious and/or unstable pre-existing medical disorder, psychiatric disorder, or other conditions that could interfere with subject’s safety, obtaining informed consent or compliance to the study procedures as determined by the referring physician in collaboration with the medical monitor.
3. Current use of prohibited medication during treatment with study drugs.
4. Chemotherapy, immunotherapy, or other anti-cancer therapy including investigational drugs within 14 days prior to the first dose of any one of the study drugs described in this study.
• Radiotherapy prior to initiation of therapy is allowed to a limited area (e.g., palliative treatment for painful bone metastases), if it is not the sole site of disease. Subjects must have completed treatment at least 14 days prior to starting study drugs, and must have recovered from all treatment-related toxicities.
5. Any contraindications (as identified by the investigator) to the doses of carboplatin and/or paclitaxel defined in the protocol
6. Any history of reduction in standard of care paclitaxel dose for peripheral neuropathy.
7. No known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs similar or related to GSK2110183.
8. No known delayed hypersensitivity reaction or idiosyncratic reaction to drugs similar to carboplatin or paclitaxel. Subjects with a history of acute hypersensitivity reactions to carboplatin or paclitaxel are allowed to enroll if their symptoms can be controlled by supportive care interventions or a desensitization protocol per the local medical practice.
9. Prior use of an investigational or licensed drug that targets AKT including perifosine.
10. Presence of active gastrointestinal disease or other condition that could affect gastrointestinal absorption (e.g. malabsorption syndrome) or predispose subject to gastrointestinal ulceration.
11. Evidence of mucosal or internal bleeding.
12. Any major surgery within the last four weeks.
13. Known active infection requiring parenteral or oral anti-infective treatment.
14. Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal or cardiac disease, unstable hypertension).
15. Subjects with brain metastases and/or leptomeningeal disease are excluded.
16. QTcF interval ≥ 470 msecs.
17. Subjects with bundle branch block or pacemaker or clinically significant ECG abnormalities including 2nd degree (Type II) or 3rd degree atrioventricular (AV) block
18. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within six months of Screening.
19. Class II, III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
20. Pregnant or lactating female.
21. Any malignancy 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I Dose Escalation
AEs, SAEs, dose reduction or delays, withdrawals due to toxicities and changes in laboratory values and vital signs
Phase II Efficacy
Overall response rate (ORR) defined as the percentage of subjects with confirmed complete response or partial response using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Continuously during Phase I and Prior to Phase II portion of the study. Phase II Timepoint is ongoing as the response of a patient will be assessed when disease assessments are done. |
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| E.5.2 | Secondary end point(s) |
Phase II Efficacy
AEs, SAEs, dose reduction or delays, withdrawals due to toxicities and changes in laboratory values and vital signs.
Response rate (RRCA 125) as defined by GCIG CA 125 criteria.
Response rate (RR) as defined by a combination of RECIST 1.1 criteria and CA 125 criteria.
PFS is defined as the interval between date of treatment and the earliest date of disease progression by either RECIST 1.1 or CA 125 or death due to any cause.
PFSRECIST is defined as the interval between date of treatment and the earliest date of disease progression by RECIST v1.1 or death due to any cause. The median PFSRECIST at 6 months will be evaluated.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As defined in the protocol |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose escalation evaluation of increasing doses of GSK2110183 administered |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| IMP will be given in combination with carboplatin and paclitaxel. |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Russian Federation |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| Subjects may continue on study drug until progression, death or unacceptable toxicity. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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