This research study is a Pilot Study, which is the first time investigators are examining
this study drug for a selected subgroup of patients with AML and MDS whose disease features a
mutation in the cohesin complex.
The FDA (the U.S. Food and Drug Administration) has approved Talazoparib as a treatment for
certain kinds of breast cancer. It is not currently approved for treating your disease.
Talazoparib is a drug that stops the activity of a protein called poly (adenosine diphosphate
[ADP]-ribose) polymerase or PARP. PARP is involved in repairing damage to the DNA within your
cells. DNA is the set of instructions found within all of your cells that tells them how to
behave. The DNA is damaged all the time by things around in the environment, and is repaired
by several different methods, one of which uses PARP. When PARP is turned off by Talazoparib
in the normal cells, other methods can still work to repair damage to DNA. However, in some
cancer cells these other methods are broken and cannot be used. When PARP is turned off by
Talazoparib in these cancer cells, DNA damage cannot be repaired and leads to the death of
the cancer cells. Talazoparib is a drug that is safe and active in breast cancer and
gynecologic cancers. However, there were no responses among 33 unselected patients with
hematologic malignancies, including 21 with AML (acute myeloid leukemia) and 4 with MDS
(myelodysplastic syndrome), when they received treatment with Talazoparib by itself. It is
not known if there were any patients with cohesin-mutations that were on the clinical trial
(these mutations are rare).
In this research study, the investigators are testing if Talazoparib is an effective
treatment for patients with AML and MDS that have a mutation in the cohesin complex. The
cohesin complex is made up of a group of proteins that are critical for normal DNA
replication activity. Mutations in the cohesin complex occur in patients with MDS/AML and may
represent a new therapeutic target. In a chemical screen experiment in a Dana-Farber Cancer
Institute laboratory, the investigators found that leukemia cells featuring a mutated cohesin
complex were sensitive to Talazoparib (meaning the leukemia cells went away after treatment
with Talazoparib) by a mechanism called synthetic lethality (this means that the lab
experiments showed that leukemia cells with a mutation in cohesin were dependent on PARP
activity to survive; when inhibiting PARP with a PARP inhibitor like Talazoparib, the
leukemia cells died). The investigators thus identified Talazoparib to be a possible
treatment for actual patients with MDS or AML that have a mutation in cohesin complex.
Inclusion Criteria:
- 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/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
HMA-based therapy.
- Participants must have measurable disease defined as 5% or more blasts (blood or bone
marrow).
- Age 18 years and older.
- ECOG performance status ≤2 (see Appendix A)
- Participants must have normal organ function as defined below:
- total bilirubin ≤ 2.5 × institutional upper limit of normal (unless considered to
be secondary to leukemia)
- AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal (unless
considered to be secondary to leukemia)
- creatinine clearance ≥ 60 mL/min/1.73 m2
- Documented pathogenic mutation in cohesin complex including a mutation in STAG2,
SMC1A, RAD21, PDS5B, or SMC3 gene from a CLIA-approved test (local testing allowed;
will be centrally confirmed). Patient must have a minimum 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
child-bearing 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
Exclusion Criteria:
- 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. If a patient is post allogeneic hematopoietic stem cell
transplant, he/she must be > 2 months from day of donor cell infusion to date of study
registration. They must be off immunosuppression therapy for at least 14 days prior to
registration (topical steroids are permitted).
- Participants who are receiving any other investigational agents.
- Participants with known 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 HIV, HCV or 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
