a study of prt1419 in patients with relapsed/refractory hematologic malignancies

Conditions: Multiple Myeloma; Acute Myeloid Leukemia; Non Hodgkin Lymphoma; Myelodysplastic Syndromes

Summary: this is a phase 1 dose-escalation study of prt1419, a myeloid cell leukemia 1 (mcl1) inhibitor, in patients with relapsed/refractory hematologic malignancies. the purpose of this study is to define the dosing schedule, maximally tolerated dose and/or estimate the optimal biological dose to be used in subsequent development of prt1419.

this is a multicenter, open-label, dose-escalation phase 1 study of prt1419, a mcl1 inhibitor, evaluating patients in two cohorts as part of a 28-day treatment cycle in adult patients with multiple myeloma (mm), non-hodgkin's lymphoma (nhl), acute myeloid leukemia (aml), chronic myelomonocytic leukemia (cmml), high-risk myelodysplastic syndrome (mds) or mds/myeloproliferative neoplasm (mpn) overlap syndrome. cohort a will evaluate prt1419 administered as monotherapy in patients with either aml, cmml and/or high-risk mds or mds/mpn overlap. cohort b will evaluate prt1419 administered as monotherapy in patients with nhl or mm. the study will employ a "3+3" dose escalation design. the dose may be escalated until a dose limiting toxicity is identified.

Eligibility criteria:
inclusion criteria: * eastern cooperative oncology group (ecog) performance status of ≤ 2 * adequate organ function (bone marrow, hepatic, renal, cardiovascular) * left ventricular ejection fraction of ≥50% * female patients of childbearing potential must have a negative pregnancy test within 7 days of the start of treatment and must agree to use a highly effective method of contraception during the trial * patients must have recovered from the effects of any prior cancer related therapy, radiotherapy or surgery (toxicity ≤ grade 1) * all patients on prior investigational agents must wait at least 5 half-lives of the agent in question, or 14 days, whichever is longer before study entry * aml patients only: pathologically confirmed diagnosis of aml as defined by the who classification and patients with targeted mutations must have been treated with appropriate therapy for their disease * white blood cell count \< 25 x 10\^9/l. hydrea or leukapheresis are permitted to meet this criterion. * cmml patients only: intermediate-2 or high risk per cmml-specific prognostic scoring system (cpss) or clinical/molecular cpss (cpss-mol) criteria. must have failed prior therapy with a hypomethylating agent. * mds patients only: intermediate, high, or very high risk by international prognostic scoring system-revised \[ipss-r\] criteria that is relapsed or refractory to approved therapies or mds/mpn overlap syndrome (displaying both fibrosis and dysplastic features). * nhl patients only: histologically or cytologically confirmed nhl, including b- and t-cell lymphomas that is relapsed or refractory or intolerant to approved therapies. must have one lesion that can be measured for response * mm patients only: measurable disease defined by one or more of the following: serum m-protein ≥ 0.5 g/dl, urine m-protein ≥ 200 mg/24 hours, serum free light chain (sflc) \> 10 mg/dl with normal serum flc ratio. presence of soft tissue plasmacytoma confirmed by imaging * nhl and mm patients only: must have the following lab values within 14 days prior to study day 1: * anc ≥1.0 x 10\^3 μl * platelet count ≥50,000 μl exclusion criteria: * known hypersensitivity to any of the components of prt1419 * female patients who are pregnant or lactating * mean qtcf interval of \>480 msec * history of heart failure, additional risk factors for arryhthmias or requiring concomitant medications that prolong the qt/qtc interval * hematopoietic stem-cell transplant \ 1 at study entry * uncontrolled intercurrent illnesses * treatment with strong inhibitors of cyp2c8 and/or p-glycoprotein for which there are no therapeutic substitutions * inflammatory disorders of the gastrointestinal tract, or subjects with gi malabsorption * hiv positive; known active hepatitis b or c * prior exposure to an mcl1 inhibitor * history of another malignancy except: * malignancy treated with curative intent with no known active disease for \>2 years at study entry * adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * adequately treated carcinoma in situ without evidence of disease * other concurrent low-grade malignancies (i.e chronic lymphocytic leukemia (rai 0)) may be considered after consultation with sponsor.