Ovarian Cancer
Conditions
Keywords
Ovarian Cancer, Pimasertib, Placebo, SAR245409
Brief summary
This is a double blind, randomized, placebo-controlled, 2-arm, Phase 2 trial investigating the efficacy and safety of combination therapy of pimasertib plus SAR245409 and pimasertib placebo administered once per day compared to pimasertib administered twice per day plus SAR245409 placebo administered once per day in participants with previously treated unresectable low-grade serous ovarian or peritoneal carcinoma or serous borderline ovarian or peritoneal tumors.
Interventions
DRUGPimasertib once daily
Pimasertib administered as oral capsule at a dose of 60 milligram (mg) once daily until disease progression, death, intolerable toxicity or withdrawal of informed consent, whichever came first.
DRUGPimasertib placebo
Placebo matching Pimasertib administered once daily in evening until disease progression, death, intolerable toxicity or withdrawal of informed consent, whichever came first.
DRUGSAR245409 placebo
Placebo matching SAR245409 administered once daily in morning until disease progression, death, intolerable toxicity or withdrawal of informed consent, whichever came first.
DRUGSAR245409
SAR245409 administered as oral capsule at a dose of 70 milligram (mg) once daily until disease progression, death, intolerable toxicity or withdrawal of informed consent, whichever came first.
DRUGPimasertib twice daily
Pimasertib administered as oral capsule at a dose of 60 milligram (mg) twice daily until disease progression, death, intolerable toxicity or withdrawal of informed consent, whichever came first.
Sponsors
Sanofi
EMD Serono
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The female participant had a diagnosis of one of the following: a) low-grade serous ovarian or peritoneal carcinoma, or grade 1 serous ovarian or peritoneal carcinoma or well-differentiated serous ovarian or peritoneal carcinoma or b) serous borderline ovarian or peritoneal tumor, ovarian or peritoneal tumor of low-malignant potential, ovarian or peritoneal atypical proliferative serous tumor that recurs as low grade serous carcinoma or has invasive peritoneal implants * The participant had at least one prior line of systemic therapy and had a tumor, which was not amenable to potentially curative surgical resection * The participant had measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 * The participant had read and understood the written informed consent form (ICF) and was willing and able to gave informed consent, fully understood the requirements of the trial and was willing to comply with all trial visits and assessments, including completion of patient-reported measures. Consent must be given before any trial related activities * Women of childbearing potential must had a negative serum pregnancy test at the screening visit * Women of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to screening, during and at least 3 months after the last dose of trial medication * Other protocol defined inclusion criteria may apply
Exclusion criteria
* The participant had previously been treated with a PI3K inhibitor and taken off treatment due to treatment related AEs * The participant had been previously treated with a Mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor * Any anti-cancer therapy or treatment incorporating chemotherapy, immunotherapy, hormonal therapy, or biologic therapy within 28 days of the start of trial treatment or within 5 times the half-life of such treatment, whichever was shorter. Treatment with nitrosoureas or mitomycin C were exceptions to this for which a treatment interval of at least 6 weeks was required * The participant had not recovered from toxicity due to prior therapy to baseline level or National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0) Grade 1 or less (except alopecia). Residual chemotherapy-induced neuropathy grade less than equal to (\<=) 2 was permitted * The participant had poor organ and marrow function as defined in the protocol * The participant had creatine phosphokinase (CPK) elevation NCI CTCAE grade greater than equal to (\>=) 2, and/or a previous history of myositis or rhabdomyolysis * The participant had difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the trial drug. Participants requiring total parenteral nutrition were to be excluded * The participant had a history of delayed healing/open wounds or diabetic ulcers * The participant had a history of congestive heart failure, unstable angina, myocardial infarction, cardiac conduction abnormalities including Fridericia corrected QT interval (QTcF) prolongation of \> 480 milliseconds (ms) or a pacemaker, clinically relevant impaired cardiovascular function (New York Heart Association (NYHA) class III/IV) or stroke within 3 months prior to enrollment * The participant had a history of retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), uveitis or retinal vein occlusion (RVO), or had other relevant abnormalities identified on screening ophthalmologic examination, which might increase the risk of serous retinal detachment (SRD) or RVO * The participant had a history of uncontrolled intercurrent illness including but not limited to an active infection, hypertension, or uncontrolled diabetes (e.g. glycosylated hemoglobin \>= 8 percent \[%\]) that would limit compliance with treatment requirements * Any previous malignancy treated with curative intent and the participant had been disease free for less than 5 years prior to randomization, with exception of carcinoma-in-situ of the cervix, squamous carcinoma of the skin, basal cell carcinoma of the skin * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Tumor Response | From randomization until disease progression or death assessed every 8 weeks up to week 32, and thereafter every 12 weeks up to 52 months | Objective tumor response was defined as the presence of at least one Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to more than (\<) 10 millimeter (mm). Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival | Time from randomization until first observation of progressive disease or death, assessed up to 52 months | PFS defined as time from randomization to first documentation of objective tumor progression.CR:Disappearance of all target lesions.Any pathological lymph nodes(whether target or non-target)must have reduction in short axis to\<10 mm.PR:At least 30% decrease in sum of diameters of target lesions,taking as reference baseline sum diameters.PD:At least a 20% increase in sum of diameters of target lesions,taking as reference smallest sum on study.In addition to relative increase of 20%,the sum also demonstrate absolute increase of at least 5 mm.SD:Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD,taking as reference smallest sum diameters while on study. PFS calculated as(Months)=first event date minus randomization or first dose date plus 1.Median PFS was computed using Kaplan-Meier estimates (product-limit estimates) and was presented with 95% confidence interval.The confidence intervals for median was calculated according to Brookmeyer and Crowley. |
| Percentage of Participants With Disease Control | Randomization until disease progression or death assessed every 8 weeks up to week 32, and thereafter every 12 weeks up to 52 months | Disease control as per RECIST v.1.1 was defined as the proportion of participants with stable disease (SD), for at least 16 weeks, PR or CR according to RECIST v1.1 criteria. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: At least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters). CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. |
| Overall Survival | Time from randomization until death, assessed up to 52 months | Overall survival (OS) was defined as the time (in months) from randomization to death. Data has been presented in terms of number participants who died and number of censored participants. |
| Health Related Quality of Life (HrQoL) Assessed Using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) | Baseline up to disease progression or withdrawal, assessed up to 52 months | EORTC QLQ-C30 is a 30-item questionnaire comprising of five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea/vomiting), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact), and a global quality of life (QoL) scale summarized from two 7-point scales (overall QoL and overall general health). Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and the individual single-items ranged in score from 0 to 100. A high scale score represents a higher response level. High score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale/item represents a high level of symptomatology/problems. |
| Health Related Quality of Life (HrQoL) Assessed Using European Organization for Research and Treatment of Cancer (EORTC) Ovarian-Specific Module Quality of Life Questionnaire Ovarian Cancer Module (QLQ-OV28) | Baseline up to disease progression or withdrawal, assessed up to 52 months | EORTC QLQ-OV28 assesses disease and treatment-related symptoms of ovarian cancer. The 28-item module comprises of 6 symptom scales (abdominal/gastrointestinal symptoms, peripheral neuropathy, other chemotherapy side-effects, hormonal symptoms, body image, attitude to disease and treatment), and sexual functioning. All of the scales and the individual single-items ranged in score from 0 to 100. Higher scores indicate a better quality of life. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Treatment and Death | First dose of study drug up to 52 months | TEAEs, Serious TEAEs and AEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.0. An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A Serious Adverse Event was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to data cut-off that were absent before treatment or that worsened relative to pretreatment state. |
| Maximum Plasma Concentration (Cmax) After Dose of Pimasertib and SAR245409 | Pre-dose Hour 0.5, 1.5, 4.5 8 post dose on Day 15, 29, 43 | — |
| Area Under the Curve (AUC) After Dose of Pimasertib and SAR245409 | Pre-dose Hour 0.5, 1.5, 4.5 8 post dose on Day 15, 29, 43 | — |
| Molecular Alterations in MAPK and/or PI3K Signaling Pathway Components/Modulators in Tumor Tissue and Blood | Screening visit (day -28 to 1) | — |
Countries
Australia, Belgium, Canada, France, Poland, Spain, United States
Participant flow
Recruitment details
First/last participants (informed consent): Sep 2013/Oct 2014. Clinical data cut off: Jan 2018.
Participants by arm
| Arm | Count |
|---|---|
| Pimasertib (Once Daily) Plus SAR245409 Participants received Pimasertib oral capsule at a dose of 60 milligram (mg) once daily along with SAR245409 oral capsule at a dose of 70 mg once daily and placebo matching to pimasertib in evening until disease progression, death, intolerable toxicity or withdrawal of informed consent, whichever came first. | 32 |
| Pimasertib (Twice Daily) Plus SAR245409 Placebo Participants received pimasertib oral capsule at a dose of 60 mg twice daily along with placebo matching to SAR245409 once daily in morning until disease progression, death, intolerable toxicity or withdrawal of informed consent, whichever came first. | 33 |
| Total | 65 |
Baseline characteristics
| Characteristic | Pimasertib (Once Daily) Plus SAR245409 | Pimasertib (Twice Daily) Plus SAR245409 Placebo | Total |
|---|---|---|---|
| Age, Continuous | 47.3 years STANDARD_DEVIATION 14.07 | 50.6 years STANDARD_DEVIATION 16.39 | 49.0 years STANDARD_DEVIATION 15.26 |
| Sex: Female, Male Female | 32 Participants | 33 Participants | 65 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 32 | 32 / 32 |
| serious Total, serious adverse events | 16 / 32 | 18 / 32 |
Outcome results
Primary
Objective Tumor Response
Objective tumor response was defined as the presence of at least one Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to more than (\<) 10 millimeter (mm). Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From randomization until disease progression or death assessed every 8 weeks up to week 32, and thereafter every 12 weeks up to 52 months
Population: ITT analysis set included all participants who had been randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pimasertib (Once Daily) Plus SAR245409 | Objective Tumor Response | 12.5 percentage of participants |
| Pimasertib (Twice Daily) Plus SAR245409 Placebo | Objective Tumor Response | 12.1 percentage of participants |
Secondary
Area Under the Curve (AUC) After Dose of Pimasertib and SAR245409
Time frame: Pre-dose Hour 0.5, 1.5, 4.5 8 post dose on Day 15, 29, 43
Population: As per changed in planned analysis the outcome measure related to pharmacokinetic parameters was not assessed.
Secondary
Health Related Quality of Life (HrQoL) Assessed Using European Organization for Research and Treatment of Cancer (EORTC) Ovarian-Specific Module Quality of Life Questionnaire Ovarian Cancer Module (QLQ-OV28)
EORTC QLQ-OV28 assesses disease and treatment-related symptoms of ovarian cancer. The 28-item module comprises of 6 symptom scales (abdominal/gastrointestinal symptoms, peripheral neuropathy, other chemotherapy side-effects, hormonal symptoms, body image, attitude to disease and treatment), and sexual functioning. All of the scales and the individual single-items ranged in score from 0 to 100. Higher scores indicate a better quality of life.
Time frame: Baseline up to disease progression or withdrawal, assessed up to 52 months
Population: Data was not collected for this outcome because as per Protocol Amendment 4 (dated 13 March 2015), the collection of patient-reported health-related quality of life outcomes was discontinued.
Secondary
Health Related Quality of Life (HrQoL) Assessed Using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30)
EORTC QLQ-C30 is a 30-item questionnaire comprising of five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea/vomiting), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact), and a global quality of life (QoL) scale summarized from two 7-point scales (overall QoL and overall general health). Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and the individual single-items ranged in score from 0 to 100. A high scale score represents a higher response level. High score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale/item represents a high level of symptomatology/problems.
Time frame: Baseline up to disease progression or withdrawal, assessed up to 52 months
Population: Data was not collected for this outcome because as per Protocol Amendment 4 (dated 13 March 2015), the collection of patient-reported health-related quality of life outcomes was discontinued.
Secondary
Maximum Plasma Concentration (Cmax) After Dose of Pimasertib and SAR245409
Time frame: Pre-dose Hour 0.5, 1.5, 4.5 8 post dose on Day 15, 29, 43
Population: As per changed in planned analysis the outcome measure related to pharmacokinetic parameters was not assessed.
Secondary
Molecular Alterations in MAPK and/or PI3K Signaling Pathway Components/Modulators in Tumor Tissue and Blood
Time frame: Screening visit (day -28 to 1)
Population: As per changed in planned analysis the outcome measure related to pharmacodynamics parameters was not assessed.
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Treatment and Death
TEAEs, Serious TEAEs and AEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.0. An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A Serious Adverse Event was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to data cut-off that were absent before treatment or that worsened relative to pretreatment state.
Time frame: First dose of study drug up to 52 months
Population: Safety population (SAF) analysis set included all participants who received at least one dose of any trial treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pimasertib (Once Daily) Plus SAR245409 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Treatment and Death | TEAE | 32 Participants |
| Pimasertib (Once Daily) Plus SAR245409 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Treatment and Death | Serious TEAE | 16 Participants |
| Pimasertib (Once Daily) Plus SAR245409 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Treatment and Death | TEAE leading to discontinuation of study treatment | 16 Participants |
| Pimasertib (Once Daily) Plus SAR245409 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Treatment and Death | Death | 2 Participants |
| Pimasertib (Twice Daily) Plus SAR245409 Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Treatment and Death | Death | 3 Participants |
| Pimasertib (Twice Daily) Plus SAR245409 Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Treatment and Death | TEAE | 32 Participants |
| Pimasertib (Twice Daily) Plus SAR245409 Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Treatment and Death | TEAE leading to discontinuation of study treatment | 12 Participants |
| Pimasertib (Twice Daily) Plus SAR245409 Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Treatment and Death | Serious TEAE | 18 Participants |
Secondary
Overall Survival
Overall survival (OS) was defined as the time (in months) from randomization to death. Data has been presented in terms of number participants who died and number of censored participants.
Time frame: Time from randomization until death, assessed up to 52 months
Population: ITT analysis set included all participants who had been randomized.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pimasertib (Once Daily) Plus SAR245409 | Overall Survival | Number for censored | 24 Participants |
| Pimasertib (Once Daily) Plus SAR245409 | Overall Survival | Number of deaths | 8 Participants |
| Pimasertib (Twice Daily) Plus SAR245409 Placebo | Overall Survival | Number of deaths | 6 Participants |
| Pimasertib (Twice Daily) Plus SAR245409 Placebo | Overall Survival | Number for censored | 27 Participants |
Secondary
Percentage of Participants With Disease Control
Disease control as per RECIST v.1.1 was defined as the proportion of participants with stable disease (SD), for at least 16 weeks, PR or CR according to RECIST v1.1 criteria. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: At least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters). CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm.
Time frame: Randomization until disease progression or death assessed every 8 weeks up to week 32, and thereafter every 12 weeks up to 52 months
Population: ITT analysis set included all participants who had been randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pimasertib (Once Daily) Plus SAR245409 | Percentage of Participants With Disease Control | 50.0 percentage of participants |
| Pimasertib (Twice Daily) Plus SAR245409 Placebo | Percentage of Participants With Disease Control | 39.4 percentage of participants |
Secondary
Progression-Free Survival
PFS defined as time from randomization to first documentation of objective tumor progression.CR:Disappearance of all target lesions.Any pathological lymph nodes(whether target or non-target)must have reduction in short axis to\<10 mm.PR:At least 30% decrease in sum of diameters of target lesions,taking as reference baseline sum diameters.PD:At least a 20% increase in sum of diameters of target lesions,taking as reference smallest sum on study.In addition to relative increase of 20%,the sum also demonstrate absolute increase of at least 5 mm.SD:Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD,taking as reference smallest sum diameters while on study. PFS calculated as(Months)=first event date minus randomization or first dose date plus 1.Median PFS was computed using Kaplan-Meier estimates (product-limit estimates) and was presented with 95% confidence interval.The confidence intervals for median was calculated according to Brookmeyer and Crowley.
Time frame: Time from randomization until first observation of progressive disease or death, assessed up to 52 months
Population: ITT analysis set included all participants who had been randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pimasertib (Once Daily) Plus SAR245409 | Progression-Free Survival | 9.99 months |
| Pimasertib (Twice Daily) Plus SAR245409 Placebo | Progression-Free Survival | 12.71 months |