Trial of Pimasertib With SAR245409 or Placebo in Ovarian Cancer

• ClinicalTrials.gov Identifier: NCT01936363
• Recruitment Status: Completed
• First Posted: September 6, 2013
• Results First Posted: April 7, 2017
• Last Update Posted: December 12, 2018
• Sponsor: EMD Serono
• Collaborator: Sanofi
• Information provided by (Responsible Party): EMD Serono

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Ovarian Cancer	Drug: Pimasertib once daily; Drug: Pimasertib placebo; Drug: SAR245409 placebo; Drug: SAR245409; Drug: Pimasertib twice daily	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 65 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase II Randomized Double Blind Placebo Controlled Trial of Combination of Pimasertib With SAR245409 or of Pimasertib With SAR245409 Placebo in Subjects With Previously Treated Unresectable Low Grade Ovarian Cancer
• Actual Study Start Date: September 30, 2013
• Actual Primary Completion Date: May 31, 2015
• Actual Study Completion Date: November 30, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pimasertib (once daily) plus SAR245409	Drug: Pimasertib 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.; Drug: Pimasertib placebo; Placebo matching Pimasertib administered once daily in evening until disease progression, death, intolerable toxicity or withdrawal of informed consent, whichever came first.; Drug: SAR245409; 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.
Experimental: Pimasertib (twice daily) plus SAR245409 placebo	Drug: SAR245409 placebo; Placebo matching SAR245409 administered once daily in morning until disease progression, death, intolerable toxicity or withdrawal of informed consent, whichever came first.; Drug: Pimasertib 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.

Outcome Measures

Primary Outcome Measures :

1. Objective Tumor Response [ 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 ]
   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 Outcome Measures :

1. Progression-Free Survival [ Time Frame: 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.
2. Percentage of Participants With Disease Control [ 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 ]
   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.
3. Overall Survival [ Time Frame: 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.
4. Health Related Quality of Life (HrQoL) Assessed Using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) [ Time Frame: 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.
5. 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) [ Time Frame: 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.
6. Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Treatment and Death [ Time Frame: 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.
7. 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 ]
8. 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 ]
9. Molecular Alterations in MAPK and/or PI3K Signaling Pathway Components/Modulators in Tumor Tissue and Blood [ Time Frame: Screening visit (day -28 to 1) ]

Eligibility Criteria

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

Criteria

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 exclusion criteria may apply

Contacts and Locations

Locations

United States, Georgia

Research site

Augusta, Georgia, United States, 30912

United States, Illinois

Research site

Chicago, Illinois, United States, 60637

United States, Indiana

Research site

Indianapolis, Indiana, United States, 46202

United States, Maryland

Research site

Silver Spring, Maryland, United States, 20910

United States, Massachusetts

Research site

Boston, Massachusetts, United States, 02114

Research site

Boston, Massachusetts, United States, 02215-5450

United States, Michigan

Research site

Ann Arbor, Michigan, United States, 48109

Research site

Detroit, Michigan, United States, 48202

United States, Missouri

Research site

Kansas City, Missouri, United States, 64111

Research site

Saint Louis, Missouri, United States, 63110

United States, Montana

Research site

Kalispell, Montana, United States, 59901

United States, New York

Research site

New York, New York, United States, 10065

United States, Ohio

Research site

Cincinnati, Ohio, United States, 45219

Research site

Columbus, Ohio, United States, 43210

Research site

Middletown, Ohio, United States, 45042

United States, Tennessee

Research site

Nashville, Tennessee, United States, 37203

United States, Texas

Research site

Houston, Texas, United States, 77030

Australia, New South Wales

Research site

Northmead, New South Wales, Australia, 2152

Australia, Queensland

Research site

Greenslopes, Queensland, Australia, 4120

Australia, Western Australia

Research site

Subiaco, Western Australia, Australia, 6008

Belgium

Research site

Kortrijk, Belgium, 8500

Research site

Leuven, Belgium, 3000

Canada, Ontario

Research site

Hamilton, Ontario, Canada, L8V 5C2

Research site

Toronto, Ontario, Canada, M4N 3M5

Canada, Quebec

Research site

Montreal, Quebec, Canada, H2L 4M1

Research site

Montreal, Quebec, Canada, H2W 1S6

Canada

Research site

Quebec, Canada, G1R 2J6

France

Research site

Bordeaux Cedex, Gironde, France, 33076

Poland

Research site

Chorzow, Poland, 41-500

Spain

Research site

Palma Mallorca, Baleares, Spain, 07198

Research site

Madrid, Spain, 28033

Research site

Madrid, Spain, 28046

Research site

Sevilla, Spain, 41013

Research site

Valencia, Spain, 46010

Sponsors and Collaborators

EMD Serono

Sanofi

Investigators

• Study Director: Medical Responsible; Merck KGaA, Darmstadt, Germany

More Information

• Responsible Party: EMD Serono
• ClinicalTrials.gov Identifier: NCT01936363
• Other Study ID Numbers: EMR 200066_012; 2013-000902-40 ( EudraCT Number )
• First Posted: September 6, 2013
• Results First Posted: April 7, 2017
• Last Update Posted: December 12, 2018
• Last Verified: November 2018

Keywords provided by EMD Serono:

Ovarian Cancer; Pimasertib; Placebo; SAR245409

Additional relevant MeSH terms:

Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Endocrine System Diseases; Gonadal Disorders; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Niacinamide; Vitamin B Complex; Vitamins; Micronutrients; Physiological Effects of Drugs