Trial Title:
Combination Therapy in Cancers With Mutations in DNA Repair Genes
NCT ID:
NCT05694715
Condition:
Metastatic Solid Tumor
BRCA1 Mutation
BRCA2 Mutation
ATM Gene Mutation
PALB2 Gene Mutation
Conditions: Official terms:
Irinotecan
Niraparib
Conditions: Keywords:
DNA Repair Gene Mutations
Small Molecule Inhibitor
Poly (ADP-ribose) polymerase inhibitor therapy (PARPi)
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Niraparib
Description:
Given orally
Arm group label:
Cohort 1 (Niraparib, Irinotecan)
Arm group label:
Cohort 2 (Niraparib, Irinotecan)
Arm group label:
Cohort 3a (Niraparib, Irinotecan)
Arm group label:
Cohort 3b (Niraparib, Irinotecan)
Arm group label:
Cohort 4a (Niraparib, Irinotecan)
Arm group label:
Cohort 4b (Niraparib, Irinotecan)
Other name:
Zejula
Other name:
Small molecule inhibitor
Intervention type:
Drug
Intervention name:
Irinotecan
Description:
Given intravenously (IV)
Arm group label:
Cohort 1 (Niraparib, Irinotecan)
Arm group label:
Cohort 2 (Niraparib, Irinotecan)
Arm group label:
Cohort 3a (Niraparib, Irinotecan)
Arm group label:
Cohort 3b (Niraparib, Irinotecan)
Arm group label:
Cohort 4a (Niraparib, Irinotecan)
Arm group label:
Cohort 4b (Niraparib, Irinotecan)
Other name:
Camptosar
Other name:
Irinotecan hydrochloride
Other name:
CPT-11
Summary:
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.
Detailed description:
This is an open label, non-randomized phase Ib dose finding study of niraparib and
irinotecan combination therapy. For this study, individuals with metastatic solid tumor
malignancies and BRCA1/2, ataxia telangiectasia mutated gene (ATM), or PALB2 mutations
will be enrolled with specific tumors of interest including gastrointestinal cancers
(e.g. colon, pancreas, gastric, cholangiocarcinoma), ovarian cancer, and breast cancer.
PRIMARY OBJECTIVES:
I. To assess safety and tolerability of niraparib and irinotecan combination therapy in
patients with metastatic solid tumor malignancies and BRCA1/2, ATM, or PALB2 mutations.
II. To determine the MTD and recommended phase II dose of niraparib with irinotecan
combination therapy.
SECONDARY OBJECTIVES:
I. To determine the preliminary efficacy of niraparib and irinotecan combination therapy
in patients with metastatic solid tumor malignancies and BRCA1/2, ATM, or PALB2
mutations.
OVERVIEW:
Participants will be treated in cohorts of size three to six, and the dosage will be
escalated if the clinical toxicity is acceptable. Participants may continue treatment
until disease progression, unacceptable toxicity, withdrawal of consent, start of new
anti-cancer therapy, or death. Participants will be followed for 30 days after study drug
discontinuation for safety and every 12 weeks (+/- 2 weeks) for up to 2 years after start
of therapy until disease progression or death from any cause (whichever occurs first).
Criteria for eligibility:
Criteria:
Inclusion 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:
a. BRCA1, BRCA2, ATM, and/or PALB2 (based upon archival tumor tissue or germ line
testing from any Clinical Laboratory Improvement Amendments (CLIA) approved lab).
This testing must occur prior to study enrollment.
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:
a. Females of childbearing potential and their male partners are advised to practice
a highly effective method of contraception during treatment with niraparib and/or
irinotecan and for 180 days following the last dose for females and 90 days
following the last dose for males. A woman is considered to be of childbearing
potential unless one of the following applies:
i. Is considered to be permanently sterile. Permanent sterilization methods include
hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
ii. Is postmenopausal, defined as no menses for 12 months without an alternative
medical cause. A high follicle-stimulating hormone (FSH) level consistently in the
postmenopausal range (30 milli-international units per millilitre (mIU/mL) or
higher) may be used to confirm a postmenopausal state in women not using hormonal
contraception or hormonal replacement therapy; however, in the absence of 12 months
of amenorrhea, a single FSH measurement is insufficient to confirm a postmenopausal
state.
b. A male participant of reproductive potential is eligible to participate if he
agrees to the following starting with the first dose of study treatment through at
least 90 days (a spermatogenesis cycle) after the last dose of study treatment:
i. refrain from donating sperm.
ii. Must agree to use a male condom (and should also be advised of the benefit for a
female partner to use a highly effective method of contraception as a condom may
break or leak).
c. Highly effective contraception is considered to be a method with a < 1% per year
failure rate. Recommendations for highly effective contraception while taking
niraparib include:
i. Ongoing use of injectable or implantable progesterone.
ii. Placement of an intrauterine device or intrauterine system.
iii. Bilateral tubal occlusion.
iv. Complete (as opposed to periodic) abstinence
. v. Male sterilization, with appropriate post-vasectomy documentation of absence of
sperm in ejaculate.
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.
Exclusion Criteria:
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
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
University of California, San Francisco
Address:
City:
San Francisco
Zip:
94143
Country:
United States
Status:
Recruiting
Contact:
Last name:
Early Phase Clinical Trials Recruitment
Phone:
877-827-3222
Email:
EarlyPhaseClinicalTrials@ucsf.edu
Contact backup:
Email:
cancertrials@ucsf.edu
Investigator:
Last name:
Pamela Munster, MD
Email:
Principal Investigator
Start date:
May 23, 2023
Completion date:
January 31, 2028
Lead sponsor:
Agency:
University of California, San Francisco
Agency class:
Other
Collaborator:
Agency:
GlaxoSmithKline
Agency class:
Industry
Source:
University of California, San Francisco
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05694715
