Recurrent Platinum-resistant Ovarian Cancer
Conditions
Keywords
cancer, ovarian, platinum-resistant
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.
Interventions
DRUGGSK2110183 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.
Sponsors
Accenture
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
Australia, Russia, United Kingdom
Participant flow
Recruitment details
Subjects were enrolled at 10 centers in 3 countries (United Kingdom, Australia, and Russia)
Pre-assignment details
As described in Statistical Analysis Plan (SAP) dated 14-Jul-2015, as there were \<10 subjects in Cohort B (n=2), data was summarized in phase 2 total column but not presented in a separate column for Cohort B.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 (Dose Escalation): GSK2110183 GSK2110183, either at 50 mg, 75 mg, 100 mg, 125 mg or 150 mg capsule by mouth daily in combination with carboplatin AUC 5 and paclitaxel 175 mg/m2 given intravenously every 3 weeks for a maximum 6 cycles. | 29 |
| Phase 2 (Treatment Group): GSK2110183 The dosing regimen identified in Phase 1 will then be evaluated in Phase 2, a single arm study focused on clinical efficacy. GSK2110183 125 mg (MTD) capsule by mouth daily in combination with carboplatin AUC 5 and paclitaxel 175 mg/m2 given intravenously every 3 weeks for a maximum 6 x 21 day cycles followed by continuous GSK2110183 150 mg capsule by mouth daily until progression, death or unacceptable toxicity. | 30 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Phase 1-Cohort 1.5: GSK2110183 75 mg | Clinical Progression | 0 | 1 | 0 | 0 | 0 | 0 |
| Phase 1-Cohort 2: GSK2110183 100 mg | Adverse Event | 0 | 0 | 2 | 0 | 0 | 0 |
| Phase 1-Cohort 3: GSK2110183 125 mg | Clinical Progression | 0 | 0 | 0 | 1 | 0 | 0 |
| Phase 1-Cohort 3: GSK2110183 125 mg | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 |
| Phase 2: GSK2110183 125 mg | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 |
| Phase 2: GSK2110183 125 mg | Clinical Progression | 0 | 0 | 0 | 0 | 0 | 6 |
| Phase 2: GSK2110183 125 mg | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Phase 1 (Dose Escalation): GSK2110183 | Phase 2 (Treatment Group): GSK2110183 | Total |
|---|---|---|---|
| Age, Customized 18 - 64 years | 18 participants | 15 participants | 33 participants |
| Age, Customized 65 - 84 years | 11 participants | 15 participants | 26 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 30 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 160.81 cm STANDARD_DEVIATION 6.609 | 160.92 cm STANDARD_DEVIATION 6.016 | 160.86 cm STANDARD_DEVIATION 6.264 |
| Region of Enrollment Australia | 13 participants | 15 participants | 28 participants |
| Region of Enrollment Russian Federation | 0 participants | 5 participants | 5 participants |
| Region of Enrollment United Kingdom | 16 participants | 10 participants | 26 participants |
| Sex/Gender, Customized Female | 29 participants | 30 participants | 59 participants |
| Weight | 68.01 kg STANDARD_DEVIATION 15.847 | 69.45 kg STANDARD_DEVIATION 15.836 | 68.74 kg STANDARD_DEVIATION 15.721 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 29 / 29 | 30 / 30 |
| serious Total, serious adverse events | 14 / 29 | 16 / 30 |
Outcome results
Primary
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.
Time frame: Every 3 weeks up to 6 months
Population: As described in SAP (dated 14-Jul-2015), data was not analyzed separately for Cohort B (n=2) as there were \<10 subjects in this group due to difficulty in enrolling Platinum-refractory ovarian cancer subjects.
Primary
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.
Time frame: Every 3 weeks up to 6 months
Population: ATS population (Phase 2-Cohort A)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 (Dose Escalation): GSK2110183 | Overall Response Rate (ORR) in Phase 2 Subjects With Recurrent Platinum-resistant Ovarian Cancer (Cohort A) | Complete Response | 7.1 Percentage of participants |
| Phase 1 (Dose Escalation): GSK2110183 | Overall Response Rate (ORR) in Phase 2 Subjects With Recurrent Platinum-resistant Ovarian Cancer (Cohort A) | Partial Response | 25.0 Percentage of participants |
| Phase 1 (Dose Escalation): GSK2110183 | Overall Response Rate (ORR) in Phase 2 Subjects With Recurrent Platinum-resistant Ovarian Cancer (Cohort A) | Stable Disease | 39.3 Percentage of participants |
| Phase 1 (Dose Escalation): GSK2110183 | Overall Response Rate (ORR) in Phase 2 Subjects With Recurrent Platinum-resistant Ovarian Cancer (Cohort A) | Progressive Disease | 14.3 Percentage of participants |
| Phase 1 (Dose Escalation): GSK2110183 | Overall Response Rate (ORR) in Phase 2 Subjects With Recurrent Platinum-resistant Ovarian Cancer (Cohort A) | Not Evaluable | 14.3 Percentage of participants |
| Phase 1 (Dose Escalation): GSK2110183 | Overall Response Rate (ORR) in Phase 2 Subjects With Recurrent Platinum-resistant Ovarian Cancer (Cohort A) | Overall Response Rate | 32.1 Percentage of participants |
Primary
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.
Time frame: Up to Week 3
Population: ATS population (Phase 1).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1: Maximum Tolerated Dose (MTD) of GSK2110183 | 125 mg |
Primary
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
Population: All Treated Subjects (ATS) in Phase 1.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade Greater Than or Equal to (≥) 3 in Severity | Fatigue | 1 Participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade Greater Than or Equal to (≥) 3 in Severity | Nausea | 3 Participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade Greater Than or Equal to (≥) 3 in Severity | Neutropenic sepsis | 1 Participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade Greater Than or Equal to (≥) 3 in Severity | Hyperglycemia | 3 Participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade Greater Than or Equal to (≥) 3 in Severity | Subjects with at Least 1 TEAE of Grade ≥3 | 26 Participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade Greater Than or Equal to (≥) 3 in Severity | Neutropenia | 12 Participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade Greater Than or Equal to (≥) 3 in Severity | Hypomagnesaemia | 6 Participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade Greater Than or Equal to (≥) 3 in Severity | Diarrhoea | 1 Participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade Greater Than or Equal to (≥) 3 in Severity | Rash Maculo-Papular | 2 Participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade Greater Than or Equal to (≥) 3 in Severity | Vomiting | 2 Participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade Greater Than or Equal to (≥) 3 in Severity | Anaemia | 3 Participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade Greater Than or Equal to (≥) 3 in Severity | Rash | 2 Participants |
Primary
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
Time frame: Up to Week 3
Population: ATS population (Phase 1)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1 Safety: Number of Subjects Reporting Adverse Events | Treatment Emergent Adverse Events (TEAEs) | 29 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1 Safety: Number of Subjects Reporting Adverse Events | Serious TEAEs | 14 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1 Safety: Number of Subjects Reporting Adverse Events | GSK2110183 Related Serious TEAEs | 7 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1 Safety: Number of Subjects Reporting Adverse Events | GSK2110183 Related TEAEs | 29 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1 Safety: Number of Subjects Reporting Adverse Events | Study Treatment Related TEAEs | 29 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1 Safety: Number of Subjects Reporting Adverse Events | TEAEs Leading to Discontinuation of GSK2110183 | 6 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1 Safety: Number of Subjects Reporting Adverse Events | TEAEs Leading to Discontinuation of Study Treatmnt | 17 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1 Safety: Number of Subjects Reporting Adverse Events | TEAEs Leading to Dose Modification of GSK2110183 | 18 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1 Safety: Number of Subjects Reporting Adverse Events | TEAEs Leading to Dose Modification of Study Trtmnt | 26 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1 Safety: Number of Subjects Reporting Adverse Events | TEAEs Leading to Death | 0 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 1 Safety: Number of Subjects Reporting Adverse Events | Dose Limiting Toxicity | 3 participants |
Secondary
ORR in Phase 1 Subjects With Recurrent Platinum-resistant Ovarian Cancer
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.
Time frame: Up to Week 3
Population: ATS population (Phase 1)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 (Dose Escalation): GSK2110183 | ORR in Phase 1 Subjects With Recurrent Platinum-resistant Ovarian Cancer | Complete Response | 0 Percentage of participants |
| Phase 1 (Dose Escalation): GSK2110183 | ORR in Phase 1 Subjects With Recurrent Platinum-resistant Ovarian Cancer | Partial Response | 24.1 Percentage of participants |
| Phase 1 (Dose Escalation): GSK2110183 | ORR in Phase 1 Subjects With Recurrent Platinum-resistant Ovarian Cancer | Stable Disease | 44.8 Percentage of participants |
| Phase 1 (Dose Escalation): GSK2110183 | ORR in Phase 1 Subjects With Recurrent Platinum-resistant Ovarian Cancer | Progressive Disease | 20.7 Percentage of participants |
| Phase 1 (Dose Escalation): GSK2110183 | ORR in Phase 1 Subjects With Recurrent Platinum-resistant Ovarian Cancer | Not Evaluable | 10.3 Percentage of participants |
| Phase 1 (Dose Escalation): GSK2110183 | ORR in Phase 1 Subjects With Recurrent Platinum-resistant Ovarian Cancer | Overall Response Rate | 24.1 Percentage of participants |
Secondary
PFS by RECIST of Subjects With Recurrent Platinum-resistant Ovarian Cancer (Phase 2-Cohort A)
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.
Time frame: From first dose until disease progression or death (approximately 36 months)
Population: ATS population ((Phase 2-Cohort A)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 (Dose Escalation): GSK2110183 | PFS by RECIST of Subjects With Recurrent Platinum-resistant Ovarian Cancer (Phase 2-Cohort A) | 7.1 Months |
Secondary
Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade ≥3 in Severity
Time frame: Up to Day 21 (Phase 2)
Population: ATS population (Phase 2)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade ≥3 in Severity | Subjects with at Least 1 TEAE of Grade ≥3 | 26 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade ≥3 in Severity | Neutropenia | 1 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade ≥3 in Severity | Hypomagnesaemia | 3 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade ≥3 in Severity | Diarrhoea | 6 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade ≥3 in Severity | Rash Maculo-Papular | 5 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade ≥3 in Severity | Vomiting | 4 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade ≥3 in Severity | Anaemia | 3 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade ≥3 in Severity | Rash | 3 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade ≥3 in Severity | Fatigue | 4 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade ≥3 in Severity | Nausea | 1 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade ≥3 in Severity | Neutropenic sepsis | 3 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade ≥3 in Severity | Hyperglycemia | 0 participants |
Secondary
Phase 2: Response Rate (RR) Defined by Gynecologic Cancer Intergroup (GCIG) CA 125
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.
Time frame: From Month 1 to 6
Population: ATS population (Phase 2)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Response Rate (RR) Defined by Gynecologic Cancer Intergroup (GCIG) CA 125 | Complete CA 125 Response | 16.7 Percentage of participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Response Rate (RR) Defined by Gynecologic Cancer Intergroup (GCIG) CA 125 | Partial CA 125 Response | 30.0 Percentage of participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Response Rate (RR) Defined by Gynecologic Cancer Intergroup (GCIG) CA 125 | Stable Response | 30.0 Percentage of participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Response Rate (RR) Defined by Gynecologic Cancer Intergroup (GCIG) CA 125 | CA 125 Progression | 0 Percentage of participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Response Rate (RR) Defined by Gynecologic Cancer Intergroup (GCIG) CA 125 | Not Evaluable | 23.3 Percentage of participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2: Response Rate (RR) Defined by Gynecologic Cancer Intergroup (GCIG) CA 125 | Response rate | 46.7 Percentage of participants |
Secondary
Phase 2 Safety: Number of Subjects Reporting Adverse Events
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
Time frame: Up to Day 51
Population: ATS population (Phase 2)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2 Safety: Number of Subjects Reporting Adverse Events | TEAEs | 30 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2 Safety: Number of Subjects Reporting Adverse Events | Serious TEAEs | 16 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2 Safety: Number of Subjects Reporting Adverse Events | GSK2110183 Related Serious TEAEs | 11 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2 Safety: Number of Subjects Reporting Adverse Events | GSK2110183 Related TEAEs | 25 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2 Safety: Number of Subjects Reporting Adverse Events | Study Treatment Related TEAEs | 30 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2 Safety: Number of Subjects Reporting Adverse Events | TEAEs Leading to Discontinuation of GSK2110183 | 9 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2 Safety: Number of Subjects Reporting Adverse Events | TEAEs Leading to Discontinuation of Study Treatmnt | 13 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2 Safety: Number of Subjects Reporting Adverse Events | TEAEs Leading to Dose Modification of GSK2110183 | 17 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2 Safety: Number of Subjects Reporting Adverse Events | TEAEs Leading to Dose Modification of Study Trtmnt | 24 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2 Safety: Number of Subjects Reporting Adverse Events | TEAEs Leading to Death | 0 participants |
| Phase 1 (Dose Escalation): GSK2110183 | Phase 2 Safety: Number of Subjects Reporting Adverse Events | Dose Limiting Toxicity | 0 participants |
Secondary
Progression Free Survival (PFS) by RECIST or Clinical Symptomatic Progression of Subjects With Recurrent Platinum-resistant Ovarian Cancer (Phase 2-Cohort A)
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.
Time frame: From first dose until disease progression or death (approximately 36 months)
Population: ATS population (Phase 2-Cohort A)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 (Dose Escalation): GSK2110183 | Progression Free Survival (PFS) by RECIST or Clinical Symptomatic Progression of Subjects With Recurrent Platinum-resistant Ovarian Cancer (Phase 2-Cohort A) | 6.5 Months |