BBI-TP-3654-102
BBI-TP-3654-102: A Study of Oral Nuvisertib (TP-3654) in Patients with Myelofibrosis
Trial summary:
This study is a Phase 1/2, multicenter, dose-escalation, open-label trial to assess safety, tolerability, pharmacokinetics and pharmacodynamics of nuvisertib (TP-3654) in patients with intermediate or high-risk primary or secondary MF.
Arm 1 will enroll patients who have been previously treated and failed on a JAK inhibitor or ineligible to receive treament with a JAK inhibitor.
Arm 2 will enroll patients who are on a stable dose of ruxolitinib, but who have either lost response or had a suboptimal or plateau in response.
Arm 3 will enroll patients who have been previously treated on JAK inhibitor (except momelotinib) that was complicated by anemia, thrombocytopenia or hematoma.
Receptor status / problem studied:
Inclusion criteria
1) Confirmed pathological diagnosis of primary myelofibrosis (PMF) or post-PV-MF/post-ET- MF as per WHO diagnostic criteria and intermediate or high-risk primary or secondary MF based on the Dynamic International Prognostic Scoring System (DIPSS).
2) Previously treated with a JAK inhibitor and failed on a JAK inhibitor or are ineligible to be treated with Ruxolitinib or Fedratinib at the discretion of the investigator.
3) Grade ≥ 2 bone marrow fibrosis, as confirmed by bone marrow biopsy within 12 weeks prior to Screening.
4) Fulfill the following laboratory parameters:
|— a) Platelet count ≥ 25 X 10^9 /L, without the assistance of growth factors or platelet transfusions.
|— b) Absolute Neutrophil Count (ANC) ≥ 1 x 10^9/L without the assistance of granulocyte growth factors.
|— c) Peripheral blood blast count < 10%.
|— d) Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
|— e) Life expectancy ≥ 3 months.
|— f) Adequate renal function, as determined by clinical laboratory tests (serum creatinine ≤ 1.5 x upper limit of normal (ULN), and calculated creatinine clearance ≥ 30 mL/min) (Cockcroft-Gault).
|— g) Adequate hepatic function (ALT/AST ≤ 3 x ULN, total bilirubin ≤ 1.5 x ULN; or ALT/AST ≤ 5 x ULN, direct bilirubin ≤ 2 x ULN if due to myelofibrosis), and coagulation ([PT and PTT] ≤ 1.5 x ULN).
|— h) Agree to provide bone marrow biopsies during the study: at baseline or within 12 weeks prior to enrollment, and every 6 months during treatment.
|— i) Splenomegaly during the screening period as demonstrated by splenic length ≥ 5 cm below the costal margin by palpation or spleen volume of ≥ 450 cm3 by Magnetic Resonance Imaging (MRI) or Computerized Tomography (CT) scan.
|— j) Show at least 2 symptoms measurable (score ≥ 1) using the MF-SAF, v4.0.
Exclusion criteria
1) Received previous systemic antineoplastic therapy (including unconjugated therapeutic antibodies, toxin immunoconjugates, ESA, and alpha-interferon) or any experimental therapy within 14 days or 5 half-lives, whichever is longer, before the first dose of study treatment.
2) Major surgery within 2 weeks before the first dose of either study drug.
3) Splenic irradiation within 6 months prior to Screening or prior splenectomy.
4) AML, MDS, or peripheral blasts ≥ 10%.
5) Prior autologous or allogeneic stem cell transplant at any time.
6) Eligible for allogeneic bone marrow or stem cell transplantation within 3 months following enrollment.
7) Experiencing electrolyte abnormalities of NCI CTCAE Grade ≥ 2 unless they can be corrected during screening and are deemed not clinically significant by the Investigator.
8) History of congestive heart failure, myocardial infarction within the past 6 months prior to Cycle 1/Day 1; left ventricular ejection fraction < 45% by echocardiogram or MUGA, unstable arrhythmia, or evidence of ischemia on electrocardiogram (ECG) within 14 days prior to Cycle 1/Day 1.
9) Corrected QT interval (using Fridericia’s correction formula) of > 450 msec in men and > 470 msec in women.
10) Central nervous system (CNS) cancer or metastases, meningeal carcinomatosis, malignant seizures, or a disease that either causes or threatens neurologic compromise (eg, unstable vertebral metastases).
11) Other invasive malignancies within the last 3 years, except non-melanoma skin cancer, and localized cured prostate and cervical cancer
Experienced portal hypertension or any of its complications.
12) Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic antimicrobial within 14 days.
13) Known bleeding diathesis or signs of uncontrolled active bleeding (hematuria, GI bleeding) other than self-limited causes of benign etiology that have been adequately investigated at the discretion of the Investigator.
14) Requiring anticoagulation with aspirin > 81mg daily, unfractionated heparin, low molecular weight heparin (LMWH), direct anti-thrombin inhibitors, or vitamin K antagonists (e.g., warfarin).
15) Severe chronic obstructive pulmonary disease with hypoxemia (defined as resting O2 saturation of < 90% breathing room air).
16) Medical condition or have undergone significant surgery to the gastrointestinal tract that could impair absorption or that could result in short bowel syndrome with diarrhea due to malabsorption.
17) Used hydroxyurea or anagrelide within 24 hours prior to the first dose.
18) Systemic steroid therapy (>10 mg daily prednisone or equivalent) within 7 days prior to the first dose of study treatment (note: topical, inhaled, nasal, and ophthalmic steroids are not prohibited).
Trial Title
BBI-TP-3654-102
Diagnosis
Myeloproliferative disorders
Type of trial
Pharmaceutical
Type of treatement
Haematology
Phase
I/II