This phase I trial studies the side effects and best dose of sapanisertib and ziv-aflibercept in treating patients with solid tumors that have come back (recurrent) and have spread to another place in the body (metastatic) or cannot be removed by surgery (unresectable). Sapanisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Ziv-aflibercept may stop the growth of solid tumors by blocking the growth of new blood vessels necessary for tumor growth. Giving sapanisertib with ziv-aflibercept may kill more tumor cells.
PRIMARY OBJECTIVE: I. To evaluate safety and tolerability, determine maximum tolerated dose (MTD) and recommend a phase II dose of the combination of MLN0128 (TAK-228) (sapanisertib) with ziv-aflibercept in patients with advanced cancers refractory to standard therapy. SECONDARY OBJECTIVES: I. To give early indication of efficacy by evaluation of tumor size. II. To evaluate v-akt murine thymoma viral oncogene homolog 1 (Akt)/mechanistic target of rapamycin (serine/threonine kinase) (mTOR) signaling and adaptive responses; testing phosphorylation levels of biomarkers such as, but not limited to, vascular endothelial growth factor (VEGF)1 and 2, AKT and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) following treatment with MLN0128 (TAK-228) and ziv-aflibercept in peripheral blood mononuclear cells (PBMCs) and biopsy samples during expansion cohort. OUTLINE: This is a dose-escalation study. Patients receive sapanisertib orally (PO) once daily (QD) on days 2-4, 9-11, 16-18, and 23-25 and ziv-aflibercept intravenously (IV) over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 4 weeks.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
83
Given PO
Given IV
M D Anderson Cancer Center
Houston, Texas, United States
Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD)
DLTs were defined as adverse events per Common Terminology Criteria for Adverse Events version 4.0, related to study agents and fulfilling one of the following criteria: Hematologic * Grade 4 neutropenia for \> 7 days * Febrile neutropenia (defined as absolute neutrophil count \[ANC\] \< 1.0 x 109/L and fever ≥ 38.5° C) or grade ≥3 infection with ANC≤1.0 x 109/L. * Platelet count \< 25,000/mm for \> 7 days Non-hematologic * Any toxicity ≥grade 3 that persists for \> 7 days, except: 1. nausea/vomiting, diarrhea and electrolyte imbalances; 2. grade 3 lab abnormalities that are asymptomatic and responsive to supportive measures and that are without clinical consequence; and 3. grade 3 hyperglycemia or grade 3 diabetes that can be stably controlled. * Delay of treatment \> 7 days due to hematologic and \> 14 days due to non-hematologic toxicity MTD is the highest dose level at which no more than 1 of 6 evaluable patients had a DLT
Time frame: DLT was assessed during Cycle 1 (28-day cycle).
Tumor Response by Change in Tumor Size From Baseline: Objective Response Rate Per RECIST v1.1
Tumor response by change in tumor size from baseline assessed by Objective response rate was defined as the percentage of patients who had complete response (CR) or partial response (PR) according to RECIST v1.1.
Time frame: At baseline and every 8 weeks. Confirmatory scans done 8 (not less than 4) weeks following initial documentation of objective response. If a patient has been on the study for 12 months, the response was evaluated every 12 weeks, assessed up to 3 years.
Tumor Response by Change in Tumor Size From Baseline: Disease Control Rate Per RECIST v1.1
Tumor response by change in tumor size from baseline assessed by Disease control rate was defined as the percentage of patients who had CR or PR or stable disease (SD) according to RECIST v1.1.
Time frame: At baseline and every 8 weeks. Confirmatory scans done 8 (not less than 4) weeks following initial documentation of objective response. If a patient has been on the study for 12 months, the response was evaluated every 12 weeks, assessed up to 3 years.
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