Umbralisib and Ruxolitinib Phosphate in Treating Patients with Primary Myelofibrosis, Post-Polycythemia Vera MF, Post-Essential Thrombocythemia MF, Myelodysplastic / Myeloproliferative Neoplasm, or Polycythemia Vera

Status: Administratively Complete

Description

This phase I trial studies the side effects and best dose of umbralisib and ruxolitinib phosphate when given together in treating patients with primary myelofibrosis, post-polycythemia vera myelofibrosis (MF), post-essential thrombocythemia MF, myelodysplastic / myeloproliferative neoplasm or polycythemia vera. Umbralisib and ruxolitinib phosphate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Eligibility Criteria

Inclusion Criteria

  • Subjects must voluntarily sign an informed consent form (ICF); and able to meet all study requirements
  • For escalation, subjects must have a pathologically confirmed diagnosis of PPV-MF, PET-MF, or PMF as per the European Hematology Association (EHA) or World Health Organization (WHO) diagnostic criteria (note that all diagnoses must include the presence of at least grade 1 marrow fibrosis according to the European Consensus on Grading of Bone Marrow Fibrosis as well as intermediate-1, intermediate-2, or high risk disease according to the International Working Group for Research and Treatment of Myelofibrosis (IWG-MRT) Dynamic International Prognostic Scoring System; 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, who have ongoing disease related symptoms (as defined by Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score [MPN-SAF TSS]), or blood counts with at least 8 weeks of 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; there are two expansion cohorts for patients with myelodysplasia/myeloproliferative neoplasm (MDS/MPN) (chronic myelomonocytic leukemia [CMML], atypical chronic myelogenous leukemia [aCML], refractory anemia with ringed sideroblasts and thrombocytosis [RARS-T] or MDS/MPN-unclassifiable [U]) which warrants treatment; patients with these diagnoses may be eligible, provided they are able to obtain ruxolitinib from commercial supply * 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)
  • 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 and anemia/thrombocytopenia assessed to be related to ruxolitinib exposure
  • 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), intrauterine device (IUD) or intrauterine system (IUS), and hormonal implants or combined oral contraceptives
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) and/or aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 3 x 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 =< 2 x ULN (if upon judgment of the treating physician, it is believed to be due to EMH related to MF)
  • Serum pancreatic amylase < 1.5 x ULN
  • Serum pancreatic lipase < 1.5 x ULN
  • Serum creatinine =< 2.5 mg/dL x ULN
  • Hemoglobin (Hgb) >= 8 g/dL
  • Platelets (Plt) >= 30,000 x 10^9/L
  • Absolute neutrophil count (ANC) >= 750/uL

Exclusion Criteria

  • Other invasive malignancies within the last 2 years, except non-melanoma skin cancer and localized cured prostate, cervical cancer, and ductal breast carcinoma in situ (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 liver function tests [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 hematologic 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 mechanistic target of rapamycin (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 or equal to 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 including systemic corticosteroids (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

Locations & Contacts

See trial information on ClinicalTrials.gov for a list of participating sites.

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To evaluate the safety of TGR1202 (umbralisib) in combination with ruxolitinib (ruxolitinib phosphate).

II. To evaluate the pharmacokinetics of TGR1202 in combination with ruxolitinib to determine the recommended phase 2 dose (RP2D).

SECONDARY OBJECTIVES:

I. To evaluate the response rate (overall response rate [ORR], complete response [CR], partial response [PR], clinical improvement [CI]) of TGR-1202 in combination with ruxolitinib in subjects with myelofibrosis (primary myelofibrosis [PMF], post-polycythemia vera myelofibrosis [PPV-MF], or post-essential thrombocytosis myelofibrosis [PET-MF]), myelodysplasia/myeloproliferative neoplasm (MDS/MPN), or polycythemia vera resistant to hydroxyurea.

II. To evaluate effect of the therapy on total symptom score Myeloproliferative Neoplasm Total Symptom Score (MPN-TSS).

EXPLORATORY OBJECTIVES:

I. To evaluate the effect of TGR-1202 on plasma cytokine levels when added to ruxolitinib.

II. To evaluate the effect of TGR-1202 on Janus kinase-2 V617F mutation (JAK2V617F) allele burden, when added to ruxolitinib.

III. To correlate signal response and safety signal with mutations found on next generation sequencing (NGS) to determine if use of NGS will allow for the discovery of biomarkers for response, non-response or toxicity.

IV. The use of computerized tomography (CT) evaluation of spleen volume for clinical improvement is an exploratory measure, which will be assessed at the end of the study.

OUTLINE: This is a 2-stage, phase I, dose-escalation study followed by a dose-expansion study.

STAGE I: This is a dose-escalation study of umbralisib.

Patients with myelofibrosis or hydroxyurea-resistant/refractory polycythemia vera (PV) who are already taking ruxolitinib phosphate, but not receiving enough benefit from their treatment receive umbralisib orally (PO) once daily (QD) and ruxolitinib phosphate PO twice daily (BID) on days 1-28.

STAGE II: This is dose-escalation study of ruxolitinib phosphate.

Patients with myelofibrosis or hydroxyurea-resistant/refractory PV who have never been on Janus kinase/signal transducers and activators of transcription (JAK-STAT) inhibitory agents receive umbralisib PO QD and ruxolitinib phosphate PO BID on days 1-28.

In both stages, courses repeat every 28 days for 1 year in the absence of disease progression or unacceptable toxicity. After 1 year of treatment, patients receiving a clinical benefit, as judged by the investigator, may continue receiving treatment.

After completion of study treatment, patients are followed up within 30 days.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Vanderbilt University / Ingram Cancer Center

Principal Investigator
Michael Robert Savona

Trial IDs

Primary ID VICC HEM 1538
Secondary IDs NCI-2015-01464
Clinicaltrials.gov ID NCT02493530