29 Jul TGR-1202 + Ruxolitinib PMF PPV-MF PET-MF MDS/MPN Polycythemia Vera Resistant to Hydroxyurea
Full Study Title: TGR-1202 + Ruxolitinib PMF PPV-MF PET-MF MDS/MPN Polycythemia Vera Resistant to Hydroxyurea
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.
- 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 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 (see Appendix C) 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); For expansion, subjects may have MDS/MPN (CMML, aCML, or MDS/MPN-U) for which the investigator warrants treatment, or who have a pathologically confirmed diagnosis of MF or PV as noted above
- Escalation Stage 1 patients: who have not achieved normalization of splenomegaly, symptomology, or blood counts with at least 8 weeks of ruxolitinib
- Escalation Stage 2 patients: who have not yet received therapy with any JAKSTAT regulators or PI3K delta inhibitors
- 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. (see Appendix E);
- 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 adequate methods of birth control throughout the study.
- 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); Direct 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
- 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 CVA, unstable angina, MI, 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 SCT 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).
- Conditions that do not permit compliance with the protocol;
- Concurrent condition that in the investigator’s opinion would jeopardize compliance with the protocol.
Study ID: NCT02493530
Medical College of Wisconsin
Laura C. Michaelis, MD
Laura C. Michaelis, MD