Have you or your loved ones been diagnosed with advanced malignant neoplasm?
You may be eligible to participate in a advanced malignant neoplasm clinical trial.
Have you or your loved ones been diagnosed with advanced malignant neoplasm? You may be eligible to participate in a advanced malignant neoplasm clinical trial.
What is a clinical trial? Is participating in a clinical trial right for you? Learn more
Advanced Malignant Neoplasm Clinical Trial in Houston TX
Have you or your loved ones been diagnosed with advanced malignant neoplasm?
You may be eligible to participate in a advanced malignant neoplasm clinical trial.
Have you or your loved ones been diagnosed with advanced malignant neoplasm? You may be eligible to participate in a advanced malignant neoplasm clinical trial.
Recruiting
Male & Female
18 Years +
This phase II trial studies how well talazoparib works in treating patients with cancers that have returned after a period of improvement, do not respond to treatment, or have spread to other parts of the body, and have alterations in the breast cancer, early onset (BRCA) genes. Talazoparib may cause tumor cells to die by blocking an enzyme that protects the tumor cells from damage.
Details for the study
Brief Title
Talazoparib in Treating Patients With Recurrent, Refractory, Advanced, or Metastatic Cancers and Alterations in the BRCA Genes
Official Title
Phase II Study of the PARP Inhibitor Talazoparib in Advanced Cancer Patients With Somatic Alterations in BRCA1/2, Mutations/Deletions in Other BRCA Pathway Genes and Germline Mutation in BRCA1/2 (Not Breast or Ovarian Cancer)
Brief Summary
This phase II trial studies how well talazoparib works in treating patients with cancers that <br /> have returned after a period of improvement, do not respond to treatment, or have spread to <br /> other parts of the body, and have alterations in the breast cancer, early onset (BRCA) genes. <br /> Talazoparib may cause tumor cells to die by blocking an enzyme that protects the tumor cells <br /> from damage.
Detailed Description
PRIMARY OBJECTIVES:
I. To determine whether the PARP inhibitor talazoparib achieves clinical benefit (complete
response [CR], partial response [PR] or stable disease [SD] > 24 weeks) in metastatic or
inoperable locally advanced or locally recurrent cancer patients who have somatic mutations
or deletions of BRCA1 or BRCA2, mutations or homozygous deletions in other BRCA pathway
genes, and germline mutations in BRCA1 or BRCA 2 with cancers other than breast or ovarian
cancer.
SECONDARY OBJECTIVES:
I. To evaluate the safety and tolerability of talazoparib in this patient population.
(Across-indication) II. To determine baseline molecular markers (deoxyribonucleic acid [DNA],
ribonucleic acid [RNA] and protein) or scores (e.g., microsatellite instability positives,
and somatic mutation burden) that may predict clinical benefit. (Within-indication) III. To
determine pharmacodynamic (PD) markers in tumor, blood and plasma that may predict outcome.
(Within-indication) IV. To determine concordance of BRCA1/2 alterations in archival tissue
and pre-treatment biopsies. (Within-indication) V. To determine concordance of genomic
alterations in tumor and circulating free DNA. (Within-indication) VI. To evaluate the
progression free survival (PFS) in patients. (Within-indication) VII. To evaluate the
duration of response (DOR) in patients. (Within-indication) VIII. To evaluate the overall
survival (OR) in patients. (Within-indication)
OUTLINE:
Patients receive talazoparib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28
days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 12
weeks for 1 year.
Treatments and/or Procedures
Talazoparib
Given PO
Laboratory biomarker analysis
Correlative studies
Pharmacological study
Correlative studies
Outcome Measures
Outcome measures are the tests that investigators perform to prove whether or not a treatment being tested in a clinical trial is having any effect.
Primary
Clinical benefit by Response Evaluation Criteria in Solid Tumors 1.1
Evaluated separately in each cohort. Calculated using posterior probabilities along with corresponding credible intervals.
Secondary
Duration of response
Calculated using the Kaplan-Meier method.
Secondary
Overall survival
Calculated using the Kaplan-Meier method.
Secondary
Progression free survival
Calculated using the Kaplan-Meier method.
Other
Baseline biopsy immunohistochemistry staining
Immunohistochemistry staining will be assessed via the H-score which can be treated as an interval-scaled variable. The concordance correlation coefficient as well as the Altman-Bland approach will be used to assess the concordance between archival immunohistochemistry staining and baseline biopsy immunohistochemistry staining. In addition, PTEN will be assessed (PTEN loss, no loss). Concordance between archival tissue and pre-treatment biopsies will be assessed using kappa statistics.
Other
Archival immunohistochemistry staining
Immunohistochemistry staining will be assessed via the H-score which can be treated as an interval-scaled variable. The concordance correlation coefficient as well as the Altman-Bland approach will be used to assess the concordance between archival immunohistochemistry staining and baseline biopsy immunohistochemistry staining. In addition, PTEN will be assessed (PTEN loss, no loss). Concordance between archival tissue and pre-treatment biopsies will be assessed using kappa statistics.
Other
Baseline proteomic signature and pharmacodynamic response by reverse phase protein array
Pharmacodynamic effect of talazoparib on proteomic signature will be assessed by reverse phase protein array and correlated with response, clinical benefit, as well as best response as percentage tumor change.
Other
Change in marker levels
The markers described yield interval-scaled values that may not be normally distributed, so differences between baseline and 2-week values will be assessed using the Wilcoxon signed-rank test.
Other
Genomic alterations in circulating free deoxyribonucleic acid
Concordance between tumor and circulating free deoxyribonucleic acid will be assessed using kappa statistics.
Other
Genomic alterations in tumor deoxyribonucleic acid
Concordance between tumor and circulating free deoxyribonucleic acid will be assessed using kappa statistics.
Other
BRCA1/2 alterations in archival tissue
Concordance between archival tissue and pre-treatment biopsies will be assessed using kappa statistics.
Other
Pharmacodynamic markers in blood and plasma that may predict outcome
Regulation of poly-adenosine triphosphate ribose activity in peripheral blood mononuclear cells will be correlated with response. Effect of treatment on proteomic profile and cell-free deoxyribonucleic acid will be assessed as exploratory endpoints.
Other
Molecular markers that may predict clinical benefit
Marker values will be compared between patients with and without clinical benefit using chi-squared or Fisher exact tests for categorically-scaled markers and Wilcoxon rank sum tests for interval- and ordinal-scaled markers. Only those significant on univariate analysis will be combined into a single logistic regression model to assess their independent effects on clinical benefit. Analyses will be performed both within and across the five cohorts.
Other
BRCA1/2 alterations in pretreatment biopsies
Concordance between archival tissue and pre-treatment biopsies will be assessed using kappa statistics.
Study Criteria
Inclusion Criteria:
- Patients with advanced or metastatic cancer that is refractory to standard therapy or
has relapsed after standard therapy
- Patients must have one of the following: somatic mutations or deletions in BRCA1 or
BRCA2; genomic alterations in other BRCA pathway genes (subcohorts: a. ATM, b. PALB2,
c. other genes, e.g. Fanconi Anemia genes, ARID1A, MER11, RAD50, NBS1, ATR;
amplification of EMSY); or germline mutation in BRCA1 or BRCA 2 (not breast or ovarian
cancer)
- Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
- Absolute neutrophil count >= 1500/mL
- Platelets >= 100,000/mL
- Hemoglobin >= 9 g/dL (or >= 5.6 mmol/L)
- Serum creatinine =< 1.5 x upper limit of normal (ULN) (or glomerular filtration rate
[GFR] >= 60 ml/min for patients with creatinine > 1.5 x ULN)
- Serum total bilirubin =< 1.5 x ULN (direct bilirubin =< ULN if total bilirubin [bili]
> 1.5 x ULN)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
ULN (or =< 5 x ULN if liver metastases [mets])
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants; activated
PTT (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as
PT or PTT is within therapeutic range of intended use of anticoagulants
- Patients must be >= 4 weeks beyond treatment with any chemotherapy or other
investigational therapy to include hormonal, biological, or targeted agents; or at
least 5 half-lives from hormonal, biological, or targeted agents, whichever is shorter
at the time of treatment initiation
- Women of child-bearing potential MUST have a negative serum or urine human chorionic
gonadotropin (HCG) test unless prior tubal ligation (>= 1 year before screening),
total hysterectomy or menopause (defined as 12 consecutive months of amenorrhea);
patients should not become pregnant or breastfeed while on this study; sexually active
patients must agree to use dual contraception for the duration of study participation
and for 120 days after the last dose of talazoparib
- Ability to understand and willingness to sign informed consent form prior to
initiation of the study and any study procedures
- Patients need to have biopsiable disease to enroll on cohort 1-2; patients eligible
for cohort 3 with a germline BRCA alteration can be enrolled even if they do not have
biopsiable disease
Exclusion Criteria:
- Patients who are pregnant or breastfeeding
- Prior treatment with a PARP inhibitor
- Known hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection
- Inability or unwillingness to swallow pills
- Active infection requiring intravenous (IV) antibiotics or other uncontrolled
intercurrent illness requiring hospitalization
- Any medical condition or diagnosis that would likely impair absorption of an orally
administered drug (e.g. gastrectomy, ileal bypass, chronic diarrhea, gastroparesis)
- Inability to comply with the study and follow-up procedures
- History of cerebrovascular accident (CVA), myocardial infarction or unstable angina
within the previous 6 months before starting therapy
- Has a known additional malignancy that is progressing or requires active treatment;
exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer
- Has a known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial
- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis; subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment; this exception does not include
carcinomatous meningitis which is excluded regardless or clinical stability