Ovarian Cancer
Conditions
Keywords
Alpelisib, olaparib, paclitaxel, pegylated liposomal doxorubicin, high grade, serous ovarian, fallopian or peritoneal cancer, no germline BRCA mutation, BRCA wild type, platinum-resistant or refractory, prior PARP inhibitor exposure, EPIK-O
Brief summary
The objective of this study was to assess the efficacy and safety of the combination of alpelisib and olaparib compared with single agent cytotoxic chemotherapy in patients with platinum resistant or refractory high-grade serous ovarian cancer, with no germline BRCA mutation detected.
Detailed description
This study included adult women with platinum resistant or refractory high-grade serous ovarian cancer, with no germline BRCA mutation detected. Participants were randomized in a 1:1 ratio to either alpelisib plus olaparib or single agent cytotoxic chemotherapy (paclitaxel or PLD) in this open-label, active controlled study. Participants continued to receive study treatment until disease progression, unacceptable toxicity that precludes further treatment, or until discontinuation of study treatment due to any other reason. After treatment discontinuation, all participants entered in the post-treatment follow-up period, which consisted of a safety follow-up visit and a 9-week post-progression visit. Once they completed the post-treatment follow-up, participants then entered the survival follow-up period.
Interventions
DRUGAlpelisib
Alpelisib was administered at 200 mg orally once daily following food on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28-day cycle
DRUGOlaparib
Olaparib was administered at 200 mg orally twice daily irrespective of meals on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28-day cycle.
DRUGPaclitaxel
Paclitaxel (80 mg/m²) was administered as a weekly intravenous infusion on Days 1, 8, 15, and 22 of each 28-day cycle.
DRUGPegylated liposomal doxorubicin (PLD)
Pegylated liposomal doxorubicin (40-50 mg/m² at physician discretion) was administered as an intravenous infusion once every 28 days starting on Cycle 1 Day 1.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Participant has histologically confirmed diagnosis of high-grade serous or high-grade endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer * Measurable disease, i.e., at least one measurable lesion per RECIST 1.1 criteria (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation) * If no measurable disease is present, the disease should be assessable by Gynecologic Cancer Intergroup criteria (GCIC) for CA-125 * Participant has no germline BRCA1/2 mutation as determined by an FDA-approved assay * Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Participant has platinum-resistant (progression within one to six months after completing platinum-based therapy) or platinum refractory disease (progression during treatment or within 4 weeks after the last dose), where platinum-based therapy is not an option, according to the GCIG 5th Ovarian Cancer Consensus Conference definitions (Wilson et al 2016). The platinum-based chemotherapy regimen does not necessarily need to be the last regimen the participant received prior to study entry * Participant must have received at least one but no more than three prior systemic treatment regimens and for whom single-agent chemotherapy is appropriate as the next line of treatment * Participant has received prior bevacizumab or is not eligible to receive bevacizumab due to medical reasons. Key
Exclusion criteria
* Participant has received prior treatment with any PI3K, mTOR or AKT inhibitor * Participant is concurrently using other anti-cancer therapy * Participant is in a state of small or large bowel obstruction or has other impairment of gastrointestinal (GI) function or GI disease * Participant has had surgery within 14 days prior to starting study drug or has not recovered from major adverse effects * Participant has not recovered from all toxicities related to prior anticancer therapies to baseline or NCI CTCAE Version 4.03 Grade ≤1. Exception to this criterion: participants with any grade of alopecia are allowed to enter the study * Participant has an established diagnosis of diabetes mellitus type I or uncontrolled type II based on fasting plasma glucose and HbA1c * Participants with liver impairment and Child Pugh score B or C * Participant has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to randomization, and who has not recovered to baseline, grade 1 or better from related adverse effects of such therapy (with the exception of alopecia) * Participant has a known hypersensitivity to any of the study drugs or excipients * Participant has a history of myelodysplastic syndrome or acute myeloid leukemia, or presents clinical and/ or laboratory features suggestive thereof. Other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Based on Blinded Independent Review Committee (BIRC) Assessment Using RECIST 1.1 Criteria | From randomization until the date of the first documented progression or death due to any cause, whichever comes first, assessed up to approximately 21 months | Progression-free survival (PFS) was defined as the time from randomization to the first documented disease progression or death from any cause, as determined by blinded independent review committee (BIRC) assessment. Participants without an event were censored at the date of their last adequate tumor assessment. Clinical deterioration without objective radiologic evidence was not considered disease progression in the primary efficacy analysis. Disease progression was defined according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as a ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (including baseline), with an absolute increase of at least 5 mm, the appearance of one or more new lesions, or unequivocal progression of non-target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From randomization until death, assessed up to approximately 44 months | Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a participant is not known to have died, then OS will be censored at the latest date the participant was known to be alive |
| Overall Response Rate (ORR) With Confirmed Response Based on BIRC Assessment According to RECIST 1.1 Criteria | Up to approximately 21 months | Overall Response Rate (ORR) was defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR) by blinded independent review committee (BIRC) assessment as per RECIST 1.1 criteria: * CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. * PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Clinical Benefit Rate (CBR) With Confirmed Response Based on BIRC Assessment According to RECIST 1.1 | Up to approximately 21 months | Clinical benefit rate (CBR) with confirmed response was defined as the percentage of participants whose best overall response was a confirmed CR or PR, or stable disease (SD) maintained for at least 24 weeks. CR, PR, and SD were determined by BIRC according to RECIST 1.1 criteria. |
| Time to Response (TTR) Based on BIRC Assessment and According to RECIST 1.1 | From the date of randomization to the first documented response, assessed through Month 12 | Time to response (TTR) was defined as the interval from randomization to the first documented occurrence of either complete response (CR) or partial response (PR), which was subsequently confirmed (using the date of initial response, not the confirmation date). CR and PR were determined based on tumor response data assessed by BIRC according to RECIST 1.1 criteria. |
| Duration of Response (DOR) With Confirmed Response Based on BIRC Assessment and According to RECIST 1.1 | From first documented response to first documented progression or death, assessed up to approximately 21 months | Duration of response (DOR) with confirmed response was calculated only for participants whose best overall response was a confirmed complete response (CR) or confirmed partial response (PR), based on tumor response data assessed by BIRC according to RECIST 1.1. The start date was the date of the first documented CR or PR (i.e., the initial response date, not the confirmation date), and the end date was the date of first documented disease progression or death due to underlying cancer. Participants without progression or cancer-related death were censored at the date of their last adequate tumor assessment. |
| Time to Definitive Deterioration of the Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Up to approximately 18 months | Performance status (PS) was evaluated using the ECOG scale, which comprises six grades (0 to 5), where 0 represents fully active and 5 represents death. Time to definitive deterioration in ECOG PS was defined as the interval from randomization to the date when ECOG PS worsened by at least one category from baseline and remained worsened. Deterioration was considered definitive if there was no subsequent improvement to the baseline category or better. Participants were censored if no definitive deterioration occurred before the earlier of: (i) the analysis cut-off date or (ii) initiation of a new anti-neoplastic therapy. The censoring date was the date of the last PS assessment prior to the cut-off or start of new therapy. |
| Number of Participants With Dose Interruptions and Dose Reductions | From randomization until end of treatment, assessed up to approximately 18 months | The number of participants with dose reductions/interruptions was assessed and summarized by study treatment. |
| Dose Intensity for Alpelisib and Olaparib | From randomization until end of treatment, assessed up to approximately 18 months | Dose intensity was computed as the ratio of actual cumulative dose received to actual duration of exposure and summarized by study treatment. |
| Dose Intensity for Paclitaxel | From randomization until end of treatment, assessed up to approximately 18 months | Dose intensity was computed as the ratio of actual cumulative dose received to actual duration of exposure and summarized by study treatment. |
| Dose Intensity for Pegylated Liposomal Doxorubicin | From randomization until end of treatment, assessed up to approximately 18 months | Dose intensity was computed as the ratio of actual cumulative dose received to actual duration of exposure and summarized by study treatment. |
| Area Under the Curve Calculated to the End of a Dosing Interval (Tau) at Steady-state (AUCtau) of Alpelisib and Olaparib | Day 8 Cycle 1 (pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dose), Day 1 on Cycle 2, 4 and 8 (pre-dose) | The AUCtau will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib |
| Area Under the Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast)of Alpelisib and Olaparib | Day 8 Cycle 1 (pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dose), Day 1 on Cycle 2, 4 and 8 (pre-dose) | The AUClast will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib |
| Maximum Concentration (Cmax) of Alpelisib and Olaparib | Day 8 Cycle 1 (pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dose), Day 1 on Cycle 2, 4 and 8 (pre-dose) | The Cmax will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib |
| Time to Reach Maximum Concentration (Tmax) of Alpelisib and Olaparib | Day 8 Cycle 1 (pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dose), Day 1 on Cycle 2, 4 and 8 (pre-dose) | The Tmax will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib |
| Time to Definitive Deterioration by 10% in FACT-O Trial Outcomes Index (TOI) Score | Baseline, up to 15 months | The Functional Assessment of Cancer Therapy-Ovarian (FACT O) is a validated instrument that evaluates quality of life in patients with ovarian cancer. The Trial Outcome Index (TOI) of the FACT-O combines Physical Well Being (PWB), Functional Well Being (FWB), and the Ovarian Cancer Subscale (OCS), and its scores range from 0 to 100, with higher scores indicating better quality of life and physical/functional status. Time to definitive deterioration by 10% in FACT O TOI is defined as the time from randomization to the first occurrence of at least a 10% worsening from baseline with no subsequent improvement above this threshold, or death. Participants without an event before analysis cut off or before starting another anticancer therapy were censored at their last adequate assessment. Time to deterioration was estimated using the Kaplan-Meier method. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Czechia, Denmark, Finland, France, Germany, Italy, Malaysia, Mexico, Netherlands, Portugal, Russia, Singapore, Slovakia, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Recruitment details
Participants were enrolled at 105 investigative sites in 15 countries.
Pre-assignment details
The study consisted of a screening period of up to 28 days.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 61 Years STANDARD_DEVIATION 9.52 |
| Eastern Cooperative Oncology Group (ECOG) performance status (PS) Grade 0: Fully active, able to carry on all pre-disease performance without restriction. | 115 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status (PS) Grade 1: Limited strenuous activity; ambulatory and able to do light or sedentary work. | 68 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status (PS) Grade 2: Self-care capable, ambulatory; no work; active >50% of waking hours. | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status (PS) Grade 3: Capable of only limited self-care; confined to bed or chair more than 50% of waking hours. | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status (PS) Grade 4: Completely disabled; cannot carry on any self-care; totally confined to bed or chair. | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status (PS) Grade 5: Dead | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status (PS) Missing | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 31 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 12 Participants |
| Race (NIH/OMB) White | 121 Participants |
| Sex: Female, Male Female | 358 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 26 / 180 | 7 / 164 | 49 / 180 | 56 / 164 |
| other Total, other adverse events | 172 / 180 | 153 / 164 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 92 / 180 | 50 / 164 | 0 / 0 | 0 / 0 |
Outcome results
None listed