Phase 1
N=146
Trial of MEK Inhibitor and PI3K/mTOR Inhibitor in Subjects With Locally Advanced or Metastatic Solid Tumors
Locally Advanced Solid Tumor · Metastatic Solid Tumor · Breast Cancer · Non Small Cell Lung Cancer · Melanoma
Bottom Line
View on ClinicalTrials.gov: NCT01390818 ↗Enrolled (actual)
146
Serious AEs
56.9%
Results posted
Mar 2017
Primary outcome: Primary: Number of Subjects With Dose Limiting Toxicities (DLT) — 0; 0; 0; 0 subjects
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 1
- Interventions
- MSC1936369B (pimasertib) (Drug); SAR245409 (PI3K and mTOR inhibitor) (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- EMD Serono
- Primary completion
- Apr 2015
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Subjects With Dose Limiting Toxicities (DLT) |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs) |
3; 3; 3; 4; 4; 3 | — |
| SECONDARY Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B) |
86.06; 188.2; 246.1; 406.9; 83.72; 232.5 | — |
| SECONDARY Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B) |
1.750; 0.765; 2.020; 1.500; 1.485; 1.550 | — |
| SECONDARY Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B) |
426.8; 734.4; 1547; 2116; 326.1; 1252 | — |
| SECONDARY Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1 |
451.6; 770.9; 1607; 2202; 503.1; 1869 | — |
| SECONDARY Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B) |
426.8; 742.1; 1547; 2116; 354.9; 1252 | — |
| SECONDARY Half-Life (t1/2) of MSC1936369B (Pimasertib) |
6.250; 4.670; 4.840; 4.800; 3.320; 4.640 | — |
| SECONDARY Total Body Clearance (CL/f) of Pimasertib (MSC1936369B) |
33.22; 38.90; 37.99; 40.88; 89.49; NA | — |
| SECONDARY Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib |
294.3; 240.2; 282.8; 283.0; 394.1; 223.8 | — |
| SECONDARY Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15 |
1.523; 1.269; 1.174; 1.364; 2.176; NA | — |
| SECONDARY Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15 |
1.525; 1.066; 1.106; 1.308; 1.467; NA | — |
| SECONDARY Maximum Observed Plasma Concentration (Cmax) for SAR245409 |
192.0; 295.7; 256.9; 224.5; 130.2; 64.22 | — |
| SECONDARY Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409 |
1.510; 1.150; 1.500; 1.500; 2.050; 1.540 | — |
| SECONDARY Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409 |
683.6; 1248; 1566; 3032; 634.0; 226.2 | — |
| SECONDARY Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409 |
746.9; 1265; 1601; 3032; 634.0; 298.6 | — |
| SECONDARY Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1 |
716.5; 1165; 1504; NA; NA; 331.2 | — |
| SECONDARY Apparent Terminal Half-Life (t1/2) of SAR245409 |
3.055; 3.300; 3.390; NA; NA; 3.310 | — |
| SECONDARY Total Body Clearance (CL/f) of SAR245409 |
41.80; 42.93; 46.54; NA; NA; 151.4 | — |
| SECONDARY Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f) |
174.8; 223.4; 238.5; NA; NA; 658.0 | — |
| SECONDARY Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15 |
1.189; 1.004; 0.9450; NA; NA; 1.800 | — |
| SECONDARY Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15 |
1.041; 0.8133; 0.8962; NA; NA; 1.336 | — |
| SECONDARY pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs) |
61.02; NA; NA; NA; NA; NA | — |
| SECONDARY pERK Concentrations in PBMCs |
6.77; NA; NA; NA; NA; NA | — |
| SECONDARY Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD) |
3; 2; 2; 3; 1; 2 | — |
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.
Eligibility Criteria
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 response evaluation criteria in solid tumors (RECIST) v1.1
- Subject is aged greater than or equal to (>=) 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 Kirsten rat sarcoma viral oncogene homolog (KRAS) or neuroblastoma RAS viral oncogene homolog (NRAS) mutated metastatic non-small cell lung cancer (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 colorectal cancer (CRC) with dual KRAS and PIK3CA mutation with no approved therapies, or
- BRAF V600E/K mutated unresectable or metastatic melanoma after progression on B-Raf proto-oncogene, serine/threonine kinase (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
Data sourced from ClinicalTrials.gov (NCT01390818). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.