Clinical Trial: TGR-1202 + Ruxolitinib PMF PPV-MF PET-MF MDS/MPN Polycythemia Vera Resistant to Hydroxyurea

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: TGR-1202 + Ruxolitinib in Subjects With Myelofibrosis, MDS/MPN, or Polycythemia Vera Resistant to Hydroxyurea

Brief Summary: This is a Phase 1, open-label, study of TGR-1202, a PI3K delta inhibitor, administered together with ruxolitinib in patients with myeloproliferative neoplasms (specifically: polycythemia vera, primary myelofibrosis, PPV-MF or PET-MF) and MDS/MPN.

Detailed Summary:

The escalation will include 2 initial sequential stages. Stage 1 will include myelofibrosis or hydroxyurea-resistant/refractory PV patients already taking therapeutic levels of ruxolitinib, but who are not achieving maximal response at the highest tolerated dose of ruxolitinib as discussed among investigators. Only TGR-1202 will be escalated in a modified 3+3 dose escalation algorithm to determine the MTD of TGR-1202 to be given with any given dose of ruxolitinib.

Stage 2 will include myelofibrosis or hydroxyurea-resistant/refractory PV patients who have never been on JAK-STAT inhibitory agents, and includes simultaneously initiation of both ruxolitinib and TGR-1202. In Stage 2, JAK Inhibitor naïve patients will receive TGR-1202 at the recommended dose established in Cohort 1, and ruxolitinib. As patients in Stage 1 will be on ruxolitinib at different doses, dose levels in Stage 2 will expand to meet requirements for safety analysis.


Sponsor: Vanderbilt-Ingram Cancer Center

Current Primary Outcome: Safety of TGR1202 in combination with ruxolitinib [ Time Frame: </=12 months ]

All patients who have received at least one dose of TGR-1202 will be included in the safety population. All clinical safety data (vital signs, routine laboratory tests, and adverse events) will be tabulated and listed. The safety and tolerability of TGR-1202 and ruxolitinib will be evaluated by means of drug-related dose limiting toxicity, adverse event (AE) reports, physical examinations and laboratory safety evaluations.


Original Primary Outcome: Safety of TGR1202 in combination with ruxolitinib [ Time Frame: Duration of the study ]

All patients who have received at least one dose of TGR-1202 will be included in the safety population. All clinical safety data (vital signs, routine laboratory tests, and adverse events) will be tabulated and listed. The safety and tolerability of TGR-1202 and ruxolitinib will be evaluated by means of drug-related dose limiting toxicity, adverse event (AE) reports, physical examinations and laboratory safety evaluations. Efficacy analyses will be exploratory in nature. Efficacy will be assessed by evaluation of the overall response rate (ORR) categorized according to the International Working Group (IWG) Criteria. All efficacy measures will be estimated with 95% confidence intervals by dose schedule and group. All efficacy and quality of life variables as assessed by the IWG-MRT criteria and MPN-SAF TSS will be tabulated with summary statistics. Change from baseline to each efficacy assessment will be assessed using the Wilcoxon Sign Rank test.


Current Secondary Outcome:

  • Overall response [ Time Frame: EOT - 12 months ]
    Number of patients in each response category, polycythemia IWG response criteria, IWG-MRT response criteria, IWG MDS/MPN response criteria summarized as follows for target lesion criteria (see IWG for additional details): complete response (CR), normalization of bone marrow, peripheral counts, spleen size, and symptoms; partial response (PR); Hematologic improvement (HI), or progressive disease (PD). Patients are categorized according to the best response achieved prior to occurrence of progressive disease, where best response hierarchy is CR>PR>HI>SD>PD.
  • Total symptom score (MPN-TSS) [ Time Frame: 16 weeks of therapy ]
    The myeloproliferative neoplasm - total symptoms score (MPN-TSS) is a validated tool in measurement in symptoms for patients with these diseases and we will measure patient reported outcomes with this validated tool
  • Blood levels of TGR1202 in combination with ruxolitinib (Pharmacokinetics) [ Time Frame: 30 days ]
    The PK parameters (including AUC (0-∞), AUC (0- τ), Cmax, tmax, λz, and t½) of TGR-1202 and ruxolitinib following will be assessed by analysis of TGR-1202 plasma concentrations during the dose escalation phase of the study.


Original Secondary Outcome:

  • Overall response [ Time Frame: EOT - 12 months ]
    Number of patients in each response category, polycythemia IWG response criteria, IWG-MRT response criteria, IWG MDS/MPN response criteria summarized as follows for target lesion criteria (see IWG for additional details): complete response (CR), normalization of bone marrow, peripheral counts, spleen size, and symptoms; partial response (PR); Hematologic improvement (HI), or progressive disease (PD). Patients are categorized according to the best response achieved prior to occurrence of progressive disease, where best response hierarchy is CR>PR>HI>SD>PD.
  • Total symptom score (MPN-TSS) [ Time Frame: 16 weeks of therapy ]
    The PK parameters (including AUC (0-∞), AUC (0- τ), Cmax, tmax, λz, and t½) of TGR-1202 and ruxolitinib following will be assessed by analysis of TGR-1202 plasma concentrations during the dose escalation phase of the study.
  • Pharmacokinetics of TGR1202 in combination with ruxolitinib [ Time Frame: 30 days ]
    The PK parameters (including AUC (0-∞), AUC (0- τ), Cmax, tmax, λz, and t½) of TGR-1202 and ruxolitinib following will be assessed by analysis of TGR-1202 plasma concentrations during the dose escalation phase of the study.


Information By: Vanderbilt-Ingram Cancer Center

Dates:
Date Received: July 1, 2015
Date Started: July 2015
Date Completion: July 2019
Last Updated: November 19, 2016
Last Verified: November 2016