Talazoparib for Cohesin-Mutated AML and MDS With Excess Blasts

NCT03974217

Last updated date
Study Location
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02115, United States
Contact
617-632-6577

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Leukemia
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

- 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
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


- 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

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Advanced Information
Descriptive Information
Brief Title  ICMJE Talazoparib for Cohesin-Mutated AML and MDS With Excess Blasts
Official Title  ICMJE A Pilot Proof-of-Concept Study of Talazoparib for Cohesin-Mutated AML and MDS With Excess Blasts
Brief Summary This research study is testing if Talazoparib is an effective treatment for patients with AML and MDS that have a mutation in the cohesin complex.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Leukemia
Intervention  ICMJE Drug: Talazoparib
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 the cells. When PARP is turned off by Talazoparib in cancer cells, DNA damage cannot be repaired and leads to the death of the cancer cells.
Other Name: Talzenna
Study Arms  ICMJE Experimental: Talazoparib
  • Talazoparib is administered orally on a daily basis
  • Hydroxyurea is allowed for up to two cycles per institutional guidelines
Intervention: Drug: Talazoparib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 3, 2019)
12
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 1, 2022
Estimated Primary Completion Date June 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jacqueline S. Garcia, MD617-632-6577[email protected]
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03974217
Other Study ID Numbers  ICMJE 19-152
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD:Yes
Plan Description:The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research
Supporting Materials:Study Protocol
Supporting Materials:Statistical Analysis Plan (SAP)
Supporting Materials:Informed Consent Form (ICF)
Time Frame:Data can be shared no earlier than 1 year following the date of publication
Access Criteria:BCH - Contact the Technology & Innovation Development Office at www.childrensinnovations.org or email [email protected] BIDMC - Contact the Beth Israel Deaconess Medical Center Technology Ventures Office at [email protected] BWH - Contact the Partners Innovations team at http://www.partners.org/innovation DFCI - Contact the Belfer Office for Dana-Farber Innovations (BODFI) at [email protected] MGH - Contact the Partners Innovations team at http://www.partners.org/innovation
Responsible Party Jacqueline Garcia, MD, Dana-Farber Cancer Institute
Study Sponsor  ICMJE Dana-Farber Cancer Institute
Collaborators  ICMJE Pfizer
Investigators  ICMJE
Principal Investigator:Jacqueline Garcia, MDDana-Farber Cancer Institute
PRS Account Dana-Farber Cancer Institute
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP