Clinical Trials /

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

NCT02493530

Description:

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.

Related Conditions:
  • Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
  • Myelofibrosis
  • Polycythemia Vera
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: TGR-1202 + Ruxolitinib PMF PPV-MF PET-MF MDS/MPN Polycythemia Vera Resistant to Hydroxyurea
  • Official Title: TGR-1202 + Ruxolitinib in Subjects With Myelofibrosis, MDS/MPN, or Polycythemia Vera Resistant to Hydroxyurea

Clinical Trial IDs

  • ORG STUDY ID: VICC HEM 1538
  • NCT ID: NCT02493530

Conditions

  • Myelofibrosis
  • Polycythemia Vera

Interventions

DrugSynonymsArms
TGR-1202Escalation and expansion
ruxolitinibJakafiEscalation and expansion

Purpose

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 Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Escalation and expansionExperimentalTGR1202 and Ruxolitinib combination
  • TGR-1202
  • ruxolitinib

Eligibility Criteria

        Inclusion Criteria:

          -  Must voluntarily sign an ICF; and must be able to meet all study requirements

          -  For escalation, subjects must have a pathologically confirmed diagnosis of PPV-MF,
             PETMF, or PMF as per the EHA or WHO diagnostic criteria (see Appendix B) (note that
             all diagnoses must include the presence of at least Grade 1 marrow fibrosis according
             to the European Consensus on Grading of BM Fibrosis as well as int-1, int-2, or high
             risk disease according to the IWG-MRT Dynamic IPSS; Patients with PV may enter the
             trial if they meet the labeled indication for ruxolitinib (eg hydroxyurea resistant or
             refractory);

          -  Escalation Stage 1 patients: who have not achieved normalization of splenomegaly,
             symptomology, or blood counts with at least 8 weeks therapy with a steady dose of
             ruxolitinib

          -  Escalation Stage 2: patients who have not yet received therapy with any JAK-STAT
             inhibitory agents or patients on at least 8 weeks of a steady dose of ruxolitinib;
             patients with exposure to other JAK-STAT inhibitory agents are not eligible. After
             discussion with the study chair or designee, patients with suboptimal response on at
             least 8 weeks of a steady dose of ruxolitinib may be allowed to de-escalate
             ruxolitinib therapy in order to enter a safety cohort which is enrolling patients at a
             lower dose; patients must receive the lower dose of ruxolitinib for at least 7
             consecutive days without event before adding TGR-1202. If the patient completed
             screening evaluation including bone marrow biopsy/aspirate prior to ruxolitinib
             de-escalation, it need not be repeated after de-escalation provided that all
             evaluation occurred within 28 days prior to the first dose of TGR-1202.

               -  For expansion, subjects may have a pathologically confirmed diagnosis of MF or PV
                  as noted above in #2. There are also two expansion cohorts for patients with
                  MDS/MPN (CMML, aCML, RARS-T or MDS/MPN-U) which warrants treatment. Patients with
                  these diagnoses may be eligible, provided they are able to obtain ruxolitinib
                  from commercial supply.

               -  A bone marrow biopsy must be performed within four weeks prior to Cycle 1 Day 1
                  treatment to establish the baseline fibrosis score, and consent is required prior
                  to that bone marrow biopsy to assure tissue is collected for protocol mandated
                  testing;

               -  Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance
                  Status of 0-2;

               -  Life expectancy of at least six months;

               -  Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic
                  treatments, excluding alopecia;

               -  Women of child bearing potential (WCBP), defined as a sexually mature woman not
                  surgically sterilized or not post-menopausal for at least 24 consecutive months
                  if ≤55 years or 12 months if >55 years, must have a negative serum pregnancy test
                  within 72 hours prior to the first dose of study drug and must agree to use
                  highly effective methods of birth control throughout the study. Highly effective
                  methods of contraception include total abstinence, sterilization of patient
                  and/or patient's partner, or use of combination of two methods, including barrier
                  methods (double barrier method is acceptable), IUD or IUS, and hormonal implants
                  or combined oral contraceptives

               -  Must have adequate organ function as demonstrated by the following:

               -  ALT (SGPT) and/or AST (SGOT) ≤ 3x upper limit of normal (ULN), or ≤ 4 x ULN (if
                  upon judgment of the treating physician, it is believed to be due to
                  extramedullary hematopoiesis [EMH] related to MF); Total bilirubin ≤ 1.5 x ULN;
                  or ≤ 2x ULN (if upon judgment of the treating physician, it is believed to be due
                  to EMH related to MF); Serum creatinine ≤ 2.5 mg/dL x ULN; Hgb ≥ 8 g/dL; Plt ≥
                  30k; ANC ≥ 750/uL

        Exclusion Criteria

          -  Patients who meet any of the following criteria will be excluded from trial entry:

          -  Other invasive malignancies within the last 2 years, except non-melanoma skin cancer
             and localized cured prostate, cervical cancer, and DCIS

          -  History of cerebral vascular accident, unstable angina, myocardial infarction, or
             ventricular arrhythmia within the last 6 months;

          -  Any serious, unstable medical or psychiatric condition that would prevent, (as judged
             by the Investigator) the subject properly providing informed consent or any condition
             which would jeopardize compliance with the protocol

          -  Known history of human immunodeficiency virus (HIV), or known active hepatitis A, B,
             or C infection (hepatitis B carriers with normal LFTs and undetectable viral loads are
             allowed);

          -  Organ transplant recipients other than bone marrow transplant;

          -  Women who are pregnant or lactating;

          -  Autologous hematologic stem cell transplant within 3 months of study entry. Allogeneic
             stem cell transplant within 6 months. Grade II, or greater, active graft versus-host
             disease.

          -  Use of an investigational drug within 21 days or 5 half-lives (whichever is shorter)
             prior to the first dose of TGR-1202. For investigational drugs for which 5 half-lives
             is less than 21 days, a minimum of 10 days between termination of the investigational
             drug and administration of TGR-1202 is required.

          -  Previous therapy with GS-1101 (CAL-101), IPI-145 or any drug that specifically
             inhibits PI3K or mTOR within last 6 months;

          -  Any major surgery, chemotherapy, or immunotherapy within the last 21 days (limited
             palliative radiation is allowed ≥ 2 weeks); concurrent hydroxyurea is allowed if less
             than 2 grams daily and on stable dose for ≥14 days prior to study entry;

          -  Patient has received wide field radiotherapy (including therapeutic radioisotopes such
             as strontium 89) ≤ 28 days or limited field radiation for palliation ≤ 14 days prior
             to starting trial medications or has not recovered from side effects of such therapy;

          -  Ongoing immunosuppressive therapy (prednisone or equivalent ≤10 mg daily allowed as
             clinically warranted). Patients are allowed to use topical or inhaled corticosteroids;

          -  Psychological, familial, sociological, or geographical conditions that do not permit
             compliance with the protocol

          -  Concurrent condition that in the investigator's opinion would jeopardize compliance
             with the protocol.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety of TGR1202 in combination with ruxolitinib
Time Frame:</=12 months
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Overall response
Time Frame:EOT - 12 months
Safety Issue:
Description: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.
Measure:Total symptom score (MPN-TSS)
Time Frame:16 weeks of therapy
Safety Issue:
Description: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
Measure:Blood levels of TGR1202 in combination with ruxolitinib (Pharmacokinetics)
Time Frame:30 days
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Vanderbilt-Ingram Cancer Center

Trial Keywords

  • MDS/MPN

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