Trial of MEK Inhibitor and PI3K/mTOR Inhibitor in Subjects With Locally Advanced or Metastatic Solid Tumors

Breast Cancer Clinical Trial

Official title:

An Open-Label, Phase Ib Dose Escalation Trial of Oral Combination Therapy With MSC1936369B and SAR245409 in Subjects With Locally Advanced or Metastatic Solid Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01390818
• Other study ID #: EMR 200066-006
• Status: Completed
• Phase: Phase 1
• First received: April 18, 2011
• Last updated: June 3, 2015
• Start date: May 2011
• Est. completion date: April 2015

Study information

• Verified date: June 2015
• Source: EMD Serono
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This research trial is testing a combination of two experimental drugs, MSC1936369B (Mitogen-activated protein extracellular signal-regulated kinase (MEK) Inhibitor) and SAR245409 (Phosphatidylinositol 3-kinase (Pi3K)/Mammalian Target of Rapamycin (mTOR) inhibitor), in the treatment of locally advanced or metastatic solid tumors. The primary purpose of the study is to determine the maximum tolerated dose of the drug combination.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 146
• Est. completion date: April 2015
• Est. primary completion date: April 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Subject with advanced solid tumors for which there is no approved therapy:

• Advanced solid tumor with diagnosed alteration in one or more of the following genes (PTEN, BRAF, KRAS, NRAS, PI3KCA, ErbB1, ErbB2, MET, RET, c-KIT, GNAQ, GNA11 and/or

• A histologically or cytologically confirmed diagnosis of one of the following solid tumors: pancreatic, thyroid, colorectal, non-small cell lung, endometrial, renal, breast, ovarian carcinoma and melanoma

• Subject with archived tumor tissue available for transfer to the Sponsor

• Subject enrolled at lower dose level cohorts and MTD expansion cohorts must have tumor available for biopsy and agree to pre-treatment and on-treatment tumor biopsies

• Subject has measurable or evaluable disease by RECIST v1.1

• Subject is aged >= 18 years

• Subjects enrolled in disease specific expansion cohorts must fulfill all the inclusion/exclusion criteria listed above with the following restriction to the Inclusion Criterion number 1:

• Relapsed or refractory KRAS or NRAS mutated metastatic NSCLC with no approved therapies, OR

• Relapsed or refractory metastatic triple negative breast cancer defined as estrogen, progesterone and HER2 negative carcinoma of the breast with no approved therapies, OR

• Relapsed or refractory metastatic CRC with dual KRAS and PIK3CA mutation with no approved therapies, OR

• BRAF V600E/K mutated unresectable or metastatic melanoma after progression on BRAF inhibitors

• Other protocol-defined inclusion criteria could apply

Exclusion Criteria:

• Subject has been previously treated with a PI3K inhibitor or a MEK inhibitor and taken off treatment due to treatment related adverse events

• Subject has received:

• Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other anti-cancer therapy within 28 days of trial drug treatment

• Any investigational agent within 28 days of trial drug treatment

• Extensive prior radiotherapy on more than 30% bone marrow reserves, or prior bone marrow/stem cell transplantation

• Subject has not recovered from toxicity due to prior therapy

• Subject has poor organ and marrow function as defined in the protocol

• Subject has a history of central nervous system metastases, unless subject has been previously treated for CNS metastases

• Subject has a history of difficulty swallowing, malabsorption or other chronic gastrointestinal disease

• Subject has a history of recent major surgery or trauma within the last 28 days.

• Subject has participated in another clinical trial within the past 30 days

• Other protocol-defined exclusion criteria could apply

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Cancer
• Carcinoma, Non-Small-Cell Lung
• Colorectal Cancer
• Locally Advanced Solid Tumor
• Melanoma
• Metastatic Solid Tumor
• Neoplasms
• Non Small Cell Lung Cancer

Intervention

Drug:
• MSC1936369B (pimasertib)
MSC1936369B (pimasertib) will be administered orally in successive 21-day cycles. Dose escalation will proceed until Maximum Tolerated Dose (MTD) is reached. Once the MTD is reached, enrollment will begin in four disease-specific expansion cohorts at either the MTD or a lower dose recommended by the Safety Monitoring Committee. The four expansion cohorts will enroll subjects with Breast Cancer, Non-Small Cell Lung Cancer (NSCLC), Melanoma, and Colorectal Cancer.
• SAR245409 (PI3K and mTOR inhibitor)
SAR245409 (PI3K and mTOR inhibitor) will be administered orally in successive 21-day cycles. Dose escalation will proceed until MTD is reached. Once the MTD is reached, enrollment will begin in four disease-specific expansion cohorts at either the MTD or a lower dose recommended by the Safety Monitoring Committee. The four expansion cohorts will enroll subjects with Breast Cancer, NSCLC, Melanoma, and Colorectal Cancer.
• MSC1936369B (pimasertib)
MSC1936369B (pimasertib) will be administered orally in successive 21-day cycles. Dose escalation will proceed until MTD is reached. The maximum tolerated dose of MSC1936369B (pimasertib) will be combined with a lower dose of SAR245409 (PI3K and mTOR inhibitor).
• SAR245409 (PI3K and mTOR inhibitor)
SAR245409 (PI3K and mTOR inhibitor) will be administered orally in successive 21-day cycles. Dose escalation will proceed until MTD is reached. The maximum tolerated dose of SAR245409 (PI3K and mTOR inhibitor) will be combined with a lower dose of MSC1936369B (pimasertib).

Locations

Country	Name	City	State
Italy	Merck Serono Research Site	Milan
Spain	Merck Serono Research Site	Madrid
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Cancer Therapy and Research Center	San Antonio	Texas
United States	Pinnacle Oncology Hematology	Scottsdale	Arizona

Sponsors (2)

Lead Sponsor	Collaborator
EMD Serono	Sanofi

Countries where clinical trial is conducted

United States,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of subjects with dose limiting toxicities	This will be used as the primary measure for determining the Maximum Tolerated Dose (MTD) of MSC1936369B and SAR245409 combination therapy.	22 months	Yes
Secondary	Number of subjects experiencing any treatment-emergent adverse events		34 months	Yes
Secondary	Pharmacokinetics parameters in plasma: Cmax, tmax, AUC (0-24), AUC (0-tau), AUC (0-infinity), t1/2, CL/f, CLss/f, Vz/f, Vss/f, Racc(AUC), and Racc(Cmax) for MSC1936369B		34 months	No
Secondary	Pharmacokinetics parameters in plasma: Cmax, tmax, AUC (0-24), AUC (0-tau), AUC (0-infinity), t1/2, CL/f, CLss/f, Vz/f, Vss/f, Racc(AUC), and Racc(Cmax) for SAR245409		34 months	No
Secondary	pS6 concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	Pharmacodynamic marker	34 months	No
Secondary	pERK concentrations in PBMCs	Pharmacodynamic marker	34 months	No
Secondary	Number of subjects with complete tumor response, partial tumor response, or stable disease	The number of subjects with a complete response or partial response based on the investigator tumor evaluations performed every 6 weeks in accordance with RECIST v1.1.	Every 6 weeks for 34 months	No