Talazoparib for the Treatment of Cohesin-Mutated Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome
- Participants must be considered ineligible to receive intensive chemotherapy by treating investigator and must have a diagnosis of one of the following: * Secondary AML (can be untreated secondary AML if previously treated for MDS, MDS/myeloproliferative neoplasm [MPN], or any MPN with any anti-leukemic therapy; or previously treated secondary AML) * Relapsed or refractory AML or relapsed/refractory AML without available approved AML therapy * MDS with a minimum history of at least 4 cycles of decitabine or 6 cycles of azacitidine or sooner if they experience intolerance/progression while on hypomethylating agent (HMA)-based therapy
- Participants must have measurable disease defined as 5% or more blasts (blood or bone marrow)
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Total bilirubin =< 2.5 x institutional upper limit of normal (unless considered to be secondary to leukemia) (within 14 days prior to the date of registration)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (unless considered to be secondary to leukemia) (within 14 days prior to the date of registration)
- Creatinine clearance >= 30 mL/min/1.73 m^2 (within 14 days prior to the date of registration)
- Documented pathogenic mutation in cohesin complex including a mutation in STAG2, SMC1A, RAD21, PDS5B, or SMC3 gene from a Clinical Laboratory Improvement Act (CLIA)-approved test (local testing allowed; will be centrally confirmed). Patient must have a minimum variant allele frequency (VAF) of 5%. Historical testing (up to 3 months) allowed for treatment start on study as long as no disease-modifying agent was received since testing
- The effects of talazoparib on the developing human fetus are unknown. For this reason and because PARP inhibitor agents are suspected to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study participation, and 4 months after completion of talazoparib administration
- Patients must have a white blood cell count < 10 K/uL by date of registration
- For women of child bearing potential only, must have a negative urine or serum pregnancy test
- Ability to understand and the willingness to sign a written informed consent document
- Participants who have had chemotherapy within 2 weeks prior to registering for the study or those who have not recovered from adverse events (to at least grade 1 with exception of alopecia) due to agents administered more than 2 weeks earlier. Patients must not have required cytoreductive therapy within 2 weeks of starting study drug except for hydroxyurea. Prior palliative radiotherapy is permitted if completed within 5 days prior to study registration and patient has no clinically significant toxicities such as mucositis or esophagitis
- No limitations to prior therapy. However, patient may not have received prior PARP inhibitor for any indication. Patients who are post allogeneic hematopoietic stem cell transplantation must be > 2 months from day of donor cell infusion to date of study registration, without evidence of active graft versus host disease (GVHD) requiring corticosteroids 1mg/kg daily or equivalent, and off immunosuppression therapy for treatment of graft-versus-host-disease for at least 14 days prior to registration. Topical steroids (eyedrops, ointment/lotion, budesonide) are permitted; prednisone 10mg daily or less or equivalent is allowed for any reason)
- Participants who are receiving any other investigational agents
- Participants with known central nervous system (CNS) leukemia
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements or compromise safety assessment, in the judgement of the investigator
- Pregnant women are excluded from this study because talazoparib is a PARP inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with talazoparib, breastfeeding should be discontinued if the mother is treated with talazoparib. These potential risks may also apply to other agents used in this study
- Patient has known active human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV)
- Patients with prior malignancy are eligible however patient must either be in remission from prior malignancy OR have inactive (note: meaning they do not require treatment) and asymptomatic disease. Maintenance therapy such as hormone therapy is allowed
I. Utilizing blast reduction as a biological marker of response to talazoparib tosylate (talazoparib) monotherapy in myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) featuring a cohesion-mutation will evaluate the proportion of patients that have >= 50% blast reduction after the first cycle of talazoparib.
I. To determine the best overall response rate (ORR) for AML (complete remission [CR] + CR with incomplete count recovery [CRi] + CR with incomplete platelet recovery [CRp] rate + partial remission [PR]) and the best ORR for MDS (CR + marrow remission + partial remission [PR] + hematologic improvement [HI]).
II. To evaluate the longitudinal effect of talazoparib on blood (for those with leukemic blasts at baseline) and bone marrow blast reduction at day 15 of cycle 1 and at the end of cycles 1, 2, and 4.
III. To evaluate for relative and absolute cohesin mutation clearance (as assessed by variant allele frequency of blood/marrow cells) on treatment.
IV. To determine the tolerability of talazoparib in AML and MDS.
I. To assess the relationship between the rate of on treatment mutation clearance and clinical response.
II. To evaluate the subclonal architecture in response to treatment by measuring mutation abundance before and after treatment.
III. To evaluate for lower scores of RAD51 foci in responders compared to non-responders to PARP inhibition in pre-treatment samples.
OUTLINE: This is a dose-escalation study.
Patients receive talazoparib tosylate orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 52 weeks.
Trial Phase Phase I
Trial Type Treatment
Dana-Farber Harvard Cancer Center
Jacqueline Suen Garcia
- Primary ID 19-152
- Secondary IDs NCI-2019-07929
- Clinicaltrials.gov ID NCT03974217