A Phase I/Ib Trial for the Evaluation of SAR260301 in Monotherapy or in Combination With Vemurafenib in Patients With Various Advanced Cancer

NCT01673737 | Completed Phase 1

• 2 other identifiers: TCD12739U1111-1129-2696
• Study Type: interventional
• Target: 75
• Locations: 2 countries
• Sites: 4

Brief Summary

Primary Objective: Part A - Monotherapy: \- To determine the maximum tolerated dose (MTD) of SAR260301 administered as monotherapy and either on a once or twice daily schedule, to patients with advanced solid tumors or lymphomas. Part B - Combination: \- To determine the maximum tolerated dose (MTD) of SAR260301 administered in combination with the recommended standard dosage of vemurafenib to patients with unresectable / metastatic v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutated melanoma. Secondary Objectives:

• To characterize the overall safety and tolerability profile of SAR260301 administered as monotherapy (Part A) and in combination with vemurafenib (Part B).
• To characterize the pharmacokinetic (PK) profile of SAR260301 administered as monotherapy (Part A) and in combination with vemurafenib (Part B) as well as vemurafenib PK in combination with SAR260301 (Part B)
• To evaluate food effect on SAR260301 PK (Part A)
• To assess preliminary antitumor activity according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1 criteria).
• To assess preliminary antitumor activity using volumetric computed tomography (CT) or magnetic resonance imaging(MRI)
• To evaluate the pharmacodynamic (PD) effects of SAR260301 on blood and tumor.
• To evaluate PK/PD relationships.
• To identify the recommended phase 2 dose of SAR260301 in combination with vemurafenib (RP2D) (Part B only)
• To assess potential induction effect of SAR260301 on cytochrome P450 (CYP) isoenzyme 3A (CYP3A) (Part A)

Conditions

Neoplasm Malignant

Outcome Measures

Primary Outcomes (2)

• Maximal tolerated dose (MTD) of SAR260301 in monotherapy (Study Part A)

  Day 28

• Maximal tolerated dose (MTD) of SAR260301 in combination with vemurafenib (Study Part B)

  Day 28

Secondary Outcomes (9)

• Number of patients with treatment emergent events

  Up to 2 years

• Assessment of PK parameters for SAR260301 and vemurafenib, including tmax, Cmax, AUC, Rac (Day 28/Day1), half-life, CL, Ctrough

  4 weeks

• Assessment of PK parameters for SAR260301 including tmax, Cmax, AUC fasting and fed (food effect)(Only part A)

  Up to 8 weeks

• Assessment of urine excretion of SAR2690301 (Part A)

  12-24 hours at Day 28

• Assessment of potential for CYP induction (4beta-hydroxycholesterol)(Part A)

  Up to 15 days

Study Arms (2)

Part A Monotherapy

EXPERIMENTAL

Dose escalation of daily or twice daily SAR260301 within a 28-day cycle, followed by an expansion phase at the maximal tolerated dose

Drug: SAR260301

Part B Combination

EXPERIMENTAL

Dose escalation of twice-daily SAR260301 within a 28-day cycle and in combination with 720 or 960 mg twice daily of Vemurafenib, followed by an expansion phase at the maximal tolerated dose of SAR260301 in combination

Drug: SAR260301; Drug: Vemurafenib

Interventions

SAR260301 DRUG

Pharmaceutical form: film-coated tablets Route of administration: oral

Part A Monotherapy; Part B Combination

Vemurafenib DRUG

Pharmaceutical form: film-coated tablets Route of administration: oral

Part B Combination

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years old
• Locally advanced or metastatic solid tumor disease as well as lymphoma for which no alternative therapy is available (Part A)
• Unresectable / metastatic BRAF-mutated melanomas, progressing on BRAF inhibitor after no more than 4 months treatment or with only partial response (\<50% change in tumor volume) after 4 months of treatment (Part B) or vemurafenib naive (Part B escalation phase only): anterior scans must be available for patients having received BRAF inhibitor prior to entry into the study.
• At least one measurable lesion by RECIST v1.1
• Archived primary tumor biopsies or surgical specimens, or biopsies of recurrence or metastasis, will be requested for all subjects for predictive markers of response analysis.

You may not qualify if:

• ECOG performance status \>1
• Concurrent treatment with any other anticancer therapy
• Patient with reproductive potential (female and male) who do not agree to use an accepted effective method of contraception during the study treatment period and for at least 6 months following completion of study treatment.
• Pregnancy or breast-feeding
• Any malignancy related to immunodeficiency virus (HIV) or solid organ transplant; history of known HIV, unresolved viral hepatitis.
• Subjects with brain metastases of non-central nervous system (CNS) primary tumors are excluded if their lesions are larger than 1 cm in the longest dimension, symptomatic or changed in size in the latest scan compared to the previous scan. Subjects must not require corticosteroid treatment or have received treatment for brain metastases for at least one month prior to study entry.
• Inadequate haematological function.
• Inadequate renal function.
• Inadequate liver function.
• Non-resolution of any prior treatment related toxicity to \< Grade 2, except for alopecia according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03.
• Any major surgery within the last 28 days.
• History of congenital platelet function defect or bleeding diathesis.
• Abnormal platelet function using platelet function assay PFA 100® including aggregation time \>122 seconds using the collagen/ADP cartridge, and/or \>183 seconds using the collagen/epinephrine cartridge.
• Current use of aspirin, clopidogrel, ticlopidine, prasugrel or ticagrelor.
• Abnormal coagulation parameters: Prothrombin time (PT)/ international normalized ratio (INR) or activated partial thromboplastin time (aPTT) \>1.3X ULN. Prophylactic but not therapeutic anticoagulants are permitted.

Sponsors & Collaborators

• Sanofi: lead

Study Sites (4)

Investigational Site Number 840001

Boston, Massachusetts, 02114, United States

Location

Investigational Site Number 840101

Boston, Massachusetts, 02115, United States

Location

Investigational Site Number 840002

Houston, Texas, 77054, United States

Location

Investigational Site Number 124001

Toronto, M5G 2M9, Canada

Location

Related Publications (1)

• Bedard PL, Davies MA, Kopetz S, Juric D, Shapiro GI, Luke JJ, Spreafico A, Wu B, Castell C, Gomez C, Cartot-Cotton S, Mazuir F, Dubar M, Micallef S, Demers B, Flaherty KT. First-in-human trial of the PI3Kbeta-selective inhibitor SAR260301 in patients with advanced solid tumors. Cancer. 2018 Jan 15;124(2):315-324. doi: 10.1002/cncr.31044. Epub 2017 Oct 4.

  PMID: 28976556 DERIVED

MeSH Terms

Conditions

Neoplasms

Interventions

2-(2-(2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl)-6-morpholin-4-yl-3H-pyrimidin-4-one; Vemurafenib

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 23, 2012
• First Posted: August 28, 2012
• Study Start: August 1, 2012
• Primary Completion: February 1, 2015
• Study Completion: February 1, 2015
• Last Updated: April 10, 2015

Record last verified: 2015-04

Locations

US (3); CA (1)