RECRUITING

Combination Therapy in Cancers With Mutations in DNA Repair Genes

Conditions

Metastatic Solid Tumor BRCA1 Mutation BRCA2 Mutation ATM Gene Mutation PALB2 Gene Mutation DNA Repair Gene Mutations Small Molecule Inhibitor Poly (ADP-ribose) polymerase inhibitor therapy (PARPi)

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

The purpose of this phase 1 clinical trials is to determine whether niraparib (a Poly (ADP-ribose) polymerase inhibitor (PARPi)) can be safely combined with irinotecan with manageable toxicity and reasonable efficacy. Emerging evidence suggest that PARPi is an effective therapeutic strategy in a wider subset of solid tumors that may have defective homologous recombination (HR) or DNA repair gene mutations. BReast CAncer gene (BRCA), partner and localizer of BRCA2 (PALB2), and various other DNA repair germline mutations predispose carriers to cancers of the breast, ovaries, pancreas, prostate and melanoma. A number of preclinical studies have demonstrated that PARP inhibitors can work as chemopotentiators. There is significant interest in this combination, and the recommended phase II dose will be used in the upcoming NCI ComboMatch trial.

Official Title

Combination Therapy of Niraparib and Irinotecan in Cancers With Mutations in DNA Repair Genes

Quick Facts

Study Start:2023-05-23

Study Completion:2028-01-31

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT05694715

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
1. Individuals 18 years of age or older. 2. Ability to understand and willingness to voluntarily sign a written informed consent document prior to any study-related assessments or procedures are conducted; and willing and able to adhere to the study visit schedule and other protocol requirements. 3. Solid tumors where topoisomerase I inhibitors have shown efficacy, including gastrointestinal tumors (e.g., colon, pancreatic, gastric cancer and cholangiocarcinoma), breast cancer, and ovarian cancer (prostate cancer is excluded), with one or more of the following DNA repair defects: 4. Presence of at least one lesion with measurable disease as defined by RECIST 1.1 criteria for response assessment 5. Advanced solid tumor malignancy without curative options 6. At least 5 half-lives or 3 weeks (whichever is shorter) must have passed since last anticancer therapy 7. The washout period for investigational agents without published half-lives should be 3 weeks since last therapy, and all treatment related toxicities must have recovered to less than grade 2. 8. Eastern Cooperative Oncology Group (ECOG) Performance Status of \<=1 (Karnofsky \> 60%; Appendix 1). 9. Adequate organ function: 1. Absolute neutrophil count (ANC) \>= 1.5 X 109/L (no growth factors allowed within 14 days of enrollment) 2. Hemoglobin (Hgb) ≥10 g/dL (no transfusion allowed within 7 days of enrollment) 3. Platelets (plt) \>= 100 x 109/L 4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<=2.5 x Upper Limit Normal (ULN), or AST and ALT \<5 x ULN in patients with known liver metastases or known primary liver tumor(s) 5. Serum total bilirubin \<= 1.5 x ULN 6. Creatinine \<1.5 x ULN, or Estimated Glomerular filtration rate (GFR) \>= 50ml/min by Cockcroft-Gault (http://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation/) 10. Must have recovered to less than Grade 2 (CTCAE v5.0) in terms of toxicity from prior treatments (excluding neuropathy which can be ≤ Grade 2, alopecia, nail changes/nail loss or other chronic minor grade 2 AEs). 11. Must be able to take oral medications. 12. Based on its mechanism of action and pre-clinical findings, irinotecan can cause fetal harm when administered to a pregnant woman. Additionally, the effects of niraparib on the developing fetus are unknown. Therefore: 13. Human immunodeficiency virus (HIV)-infected individuals on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. 14. For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. 15. Individuals with a history of hepatitis C virus (HCV) infection must have been treated and cured. For individuals with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.	1. Any significant medical condition, laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study at clinician's discretion and not otherwise stated below. 2. Prior allergic reaction to PARP inhibitor or irinotecan or their excipients. Prior PARP inhibitor or irinotecan (or topoisomerase 1 inhibitors) use is allowed. 3. Individuals with known toxicity to irinotecan (e.g., grade 3 or 4 neutropenia) or suspected sensitivity. 4. Individuals with homozygous or compound heterozygous UGT1A1 polymorphisms (e.g., alleles \28/\28, \6/\6, or \6/\28) predicted to be associated with medium-to-high risk of irinotecan-related toxicity 5. Individuals receiving any other investigational agents concurrently with the study drugs within 3 weeks or 5 half-lives, whichever is shorter, of the first dose of therapy preceding the study. 6. Participants with unstable brain metastases are excluded. Patients with a history of brain metastases (\>1cm) are permitted to enroll if they have been treated and have been stable for a minimum of one month on imaging. Patients may not currently receive steroids for their brain metastases. Patients with small, asymptomatic brain metastases (\<1cm) may enroll. 7. Individuals with a second primary malignancy 8. Individuals with a prior history of posterior reversible encephalopathy syndrome (PRES) 9. Individuals with systolic blood pressure \>140 mmHg or diastolic blood pressure \>90 mmHg that has not been adequately treated or controlled 10. History of a malabsorption syndrome or uncontrolled nausea, vomiting, or diarrhea that may interfere with the absorption of oral study medication in the opinion of the investigator. 11. Known or suspected diagnosis of Myelodysplastic syndromes (MDS) or Acute myeloid leukemia (AML). 12. Known Gilbert's disease 13. Individuals who are pregnant and/or breast feeding, or expecting to conceive children while receiving study treatment and/or for up to 180 days after the last dose of study treatment. 14. Inability to comply with study procedures or unwilling to use adequate highly effective contraception

Inclusion Criteria

Exclusion Criteria

1. Individuals 18 years of age or older.
2. Ability to understand and willingness to voluntarily sign a written informed consent document prior to any study-related assessments or procedures are conducted; and willing and able to adhere to the study visit schedule and other protocol requirements.
3. Solid tumors where topoisomerase I inhibitors have shown efficacy, including gastrointestinal tumors (e.g., colon, pancreatic, gastric cancer and cholangiocarcinoma), breast cancer, and ovarian cancer (prostate cancer is excluded), with one or more of the following DNA repair defects:
4. Presence of at least one lesion with measurable disease as defined by RECIST 1.1 criteria for response assessment
5. Advanced solid tumor malignancy without curative options
6. At least 5 half-lives or 3 weeks (whichever is shorter) must have passed since last anticancer therapy
7. The washout period for investigational agents without published half-lives should be 3 weeks since last therapy, and all treatment related toxicities must have recovered to less than grade 2.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of \<=1 (Karnofsky \> 60%; Appendix 1).
9. Adequate organ function:
1. Absolute neutrophil count (ANC) \>= 1.5 X 109/L (no growth factors allowed within 14 days of enrollment)
2. Hemoglobin (Hgb) ≥10 g/dL (no transfusion allowed within 7 days of enrollment)
3. Platelets (plt) \>= 100 x 109/L
4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<=2.5 x Upper Limit Normal (ULN), or AST and ALT \<5 x ULN in patients with known liver metastases or known primary liver tumor(s)
5. Serum total bilirubin \<= 1.5 x ULN
6. Creatinine \<1.5 x ULN, or Estimated Glomerular filtration rate (GFR) \>= 50ml/min by Cockcroft-Gault (http://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation/)
10. Must have recovered to less than Grade 2 (CTCAE v5.0) in terms of toxicity from prior treatments (excluding neuropathy which can be ≤ Grade 2, alopecia, nail changes/nail loss or other chronic minor grade 2 AEs).
11. Must be able to take oral medications.
12. Based on its mechanism of action and pre-clinical findings, irinotecan can cause fetal harm when administered to a pregnant woman. Additionally, the effects of niraparib on the developing fetus are unknown. Therefore:
13. Human immunodeficiency virus (HIV)-infected individuals on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
14. For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
15. Individuals with a history of hepatitis C virus (HCV) infection must have been treated and cured. For individuals with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

1. Any significant medical condition, laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study at clinician's discretion and not otherwise stated below.
2. Prior allergic reaction to PARP inhibitor or irinotecan or their excipients. Prior PARP inhibitor or irinotecan (or topoisomerase 1 inhibitors) use is allowed.
3. Individuals with known toxicity to irinotecan (e.g., grade 3 or 4 neutropenia) or suspected sensitivity.
4. Individuals with homozygous or compound heterozygous UGT1A1 polymorphisms (e.g., alleles \*28/\*28, \*6/\*6, or \*6/\*28) predicted to be associated with medium-to-high risk of irinotecan-related toxicity
5. Individuals receiving any other investigational agents concurrently with the study drugs within 3 weeks or 5 half-lives, whichever is shorter, of the first dose of therapy preceding the study.
6. Participants with unstable brain metastases are excluded. Patients with a history of brain metastases (\>1cm) are permitted to enroll if they have been treated and have been stable for a minimum of one month on imaging. Patients may not currently receive steroids for their brain metastases. Patients with small, asymptomatic brain metastases (\<1cm) may enroll.
7. Individuals with a second primary malignancy
8. Individuals with a prior history of posterior reversible encephalopathy syndrome (PRES)
9. Individuals with systolic blood pressure \>140 mmHg or diastolic blood pressure \>90 mmHg that has not been adequately treated or controlled
10. History of a malabsorption syndrome or uncontrolled nausea, vomiting, or diarrhea that may interfere with the absorption of oral study medication in the opinion of the investigator.
11. Known or suspected diagnosis of Myelodysplastic syndromes (MDS) or Acute myeloid leukemia (AML).
12. Known Gilbert's disease
13. Individuals who are pregnant and/or breast feeding, or expecting to conceive children while receiving study treatment and/or for up to 180 days after the last dose of study treatment.
14. Inability to comply with study procedures or unwilling to use adequate highly effective contraception

Contacts and Locations

Study Contact

Early Phase Cancer Clinical Trials Recruitment

CONTACT

877-827-3222

EarlyPhaseClinicalTrials@ucsf.edu

Principal Investigator

Pamela Munster, MD

PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Study Locations (Sites)

University of California, San Francisco

San Francisco, California, 94143

United States

Collaborators and Investigators

Sponsor: University of California, San Francisco

Pamela Munster, MD, PRINCIPAL_INVESTIGATOR, University of California, San Francisco

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2023-05-23

Study Completion Date2028-01-31

Study Record Updates

Study Start Date2023-05-23

Study Completion Date2028-01-31

Terms related to this study

Keywords Provided by Researchers

DNA Repair Gene Mutations
Small Molecule Inhibitor
Poly (ADP-ribose) polymerase inhibitor therapy (PARPi)

Additional Relevant MeSH Terms

Metastatic Solid Tumor
BRCA1 Mutation
BRCA2 Mutation
ATM Gene Mutation
PALB2 Gene Mutation