Dose Escalation Study of Nelfinavir Plus MLN9708 in Patients With Advanced Solid Tumors or Lymphoma
- Registration Number
- NCT03422874
- Lead Sponsor
- Dartmouth-Hitchcock Medical Center
- Brief Summary
This is an open label, dose escalation, phase I study of the combination of MLN9708 plus Nelfinavir.
- Detailed Description
This is an open label, dose escalation, phase I study of the combination of MLN9708 MLN9708 plus Nelfinavir. It will use a 3+3 cohort design to determine the maximum tolerated dose of the combination, which will be defined as the highest dose cohort where \< 1/6 patients develop a dose limiting toxicity. The maximum tolerated dose cohort will be expanded to have at least 6 patients with biopsiable tumors who undergo pretreatment and post treatment tumor biopsies for molecular pharmacodynamic markers.
Recruitment & Eligibility
- Status
- WITHDRAWN
- Sex
- All
- Target Recruitment
- Not specified
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Nelfinavir plus MLN9708 MLN9708 Both Nelfinavir and MLN9708 will be given orally (by mouth). MLN9708 will be given as 3 mg orally twice weekly. Study drugs will be administered on 21-day treatment cycles. All cycles are 21 days. During the first cycle of MLN9708 only will initially be administered orally at a fixed dose of 3mg twice weekly for 2 weeks, on Mondays and Thursdays during this treatment cycle. During the third week there will be no study combination drug therapy(for Cycle 1 only). During Cycles 2 and 3, MLN9708 administered twice weekly on Mondays and Thursdays for the first 2 weeks of Cycles 2 and 3. Nelfinavir (escalating cohorts \[1250mg, 1875mg, 2500mg, 3125mg\]) will be administered orally twice daily in the dose cohorts listed. Nelfinavir plus MLN9708 Nelfinavir Both Nelfinavir and MLN9708 will be given orally (by mouth). MLN9708 will be given as 3 mg orally twice weekly. Study drugs will be administered on 21-day treatment cycles. All cycles are 21 days. During the first cycle of MLN9708 only will initially be administered orally at a fixed dose of 3mg twice weekly for 2 weeks, on Mondays and Thursdays during this treatment cycle. During the third week there will be no study combination drug therapy(for Cycle 1 only). During Cycles 2 and 3, MLN9708 administered twice weekly on Mondays and Thursdays for the first 2 weeks of Cycles 2 and 3. Nelfinavir (escalating cohorts \[1250mg, 1875mg, 2500mg, 3125mg\]) will be administered orally twice daily in the dose cohorts listed.
- Primary Outcome Measures
Name Time Method Maximum Tolerated Dose (MTD) of nelfinavir Approximately 1 year to establish MTD If 0/3 patients experience dose limiting toxicity, 3 patients will be treated at the next dose level. If dose limiting toxicity attributable to the study drug(s) is experienced in exactly 1/3 patients, 3 more patients (for a total of 6) will be treated at that dose level. If no additional dose limiting toxicity is observed at the expanded dose level (i.e. 1/6 with dose limiting toxicity), the dose will be escalated. Escalation will terminate as soon as two or more patients experience any dose limiting toxicity attributable to the study drug(s), at a given dose level. If 2 or more dose limiting toxicities are observed in any cohort, no further escalation will take place, and the Maximum Tolerated Dose will have been exceeded.
The toxicity of MLN9708 when combined with nelfinavir based on CTCAE grading criteria v. 4.0 Approximately 18-24 months to observe toxicity The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by NCI Revised Common Toxicity Criteria and nadir or maximum values for the laboratory measures), time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course.
- Secondary Outcome Measures
Name Time Method The anti-tumor activity of the MLN9708/Nelfinavir The study as a whole is estimated to be completed in 18-24 months. Disease assessments, including radiological imagining will occur initially after 9 weeks of therapy and then every 6 weeks thereafter.
Pharmacokinetics of both MLN9708 and nelfinavir based on parameters estimated using WinNonLin The study as a whole is estimated to be completed in 18-24 months. MLN2238 concentrations-time data will be plotted on a semi-logarithmic plot and the decay of the drug concentrations over time inspected. The data will initially be analyzed using a non-compartmental and the primary pharmacokinetic parameters estimated using WinNonLin.
Pharmacodynamics of MLN9708 based on peripheral blood mononuclear cells (PBMCs) The study as a whole is estimated to be completed in 18-24 months. To explore the effect of nelfinavir on the pharmacodynamics of MLN9708 (as assessed by β1 and β5 inhibition in peripheral blood mononuclear cells (PBMCs), ATF-3, CHOP and GADD34 up-regulation in PBMCs.
Pharmacodynamics of MLN9708 based on tumor tissue The study as a whole is estimated to be completed in 18-24 months. To explore the effect of nelfinavir on the pharmacodynamics of MLN9708 based on tumor tissue apoptosis induction as detected by TUNEL stain, and activated caspase-3 cleavage in primary tumors.
Trial Locations
- Locations (1)
Dartmouth-Hitchcock Medical Center
🇺🇸Lebanon, New Hampshire, United States