Niraparib Maintenance Treatment in mCRC With a Partial o Complete Response After Oxaliplatin-based Induction Therapy (Bohème)

Ospedale Policlinico San Martino

Status and phase

Withdrawn

Phase 2

Conditions

Metastatic Colorectal Cancer

Treatments

Drug: Niraparib

Study type

Interventional

Funder types

Other

Identifiers

NCT05412706

Bohème

Details and patient eligibility

About

Colorectal Cancer ranks third among the most frequent malignancies representing a leading cause of cancer-related death worldwide. The constant improvement in the "continuum of care" of metastatic colorectal cancer (mCRC) patients led to a median overall survival of about 30-36 months.

Due to the cumulative toxicities of first-line combinations of chemotherapy and biological agents, discontinuation or intermittent chemotherapy or maintenance strategies have been investigated in clinical trials. After a 4 to 6-month induction treatment with bevacizumab plus doublet or triplet regimens, a fluoropyrimidine plus bevacizumab is regarded as the optimal maintenance regimen. Little evidence is available on the role of maintenance with anti-EGFR agents.

A recent systematic review and network meta-analysis of 12 relevant randomized clinical trials comprising 5540 patients with mCRC showed that a maintenance strategy with a fluoropyrimidine, with or without the addition of bevacizumab, is preferred. However, given the lack of a clear overall survival benefit, shared decision-making should include observation as an acceptable alternative.

Poly(ADP)-ribose polymerase (PARP) inhibitors are now approved for breast, ovarian and pancreatic cancers. Evidence suggests that PARP inhibitors are more effective in tumors harboring homologous recombination DNA damage repair (HRR) deficiency and platinum sensitivity may be used a surrogate marker of HRD and therefore of PARP-inhibitors efficacy. An extensive Next Generation Sequencing analysis revealed that 15% of mCRC samples harbors mutations in genes involved in the HRR pathway. Several clinical trials are ongoing to test PARP inhibitors either alone or in combination in mCRC patients. The originality of this trial is to investigate PARPi in the maintenance setting.

Pre-clinical evidence showed that PARP blockade after initial oxaliplatin response delayed disease progression in mCRC carrying Kirsten Rat Sarcoma and BRAF mutations, suggesting that maintenance treatment with PARP inhibitors warrants further clinical investigation in mCRC patients who respond to oxaliplatin-containing induction treatment.

The main objective of this trial is to investigate the efficacy of anti-PARP inhibition as maintenance treatment in mCRC patients who obtained a complete or partial response after 4-month induction treatment with oxaliplatin-based double or triplet plus biologic agents.

Full description

Multicenter phase II no profit study investigating the disease-free survival efficacy of niraparib as maintenance treatment in 46 patients with metastatic colorectal cancer with partial or complete response after oxaliplatin-based induction therapy.

The study also includes translational research objectives.

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Signed informed consent
Age ≥ 18 years at time of study entry
Histologically confirmed diagnosis of Stage IV colorectal adenocarcinoma
Disease evaluation with proven Complete Response or Partial Response according to RECIST v 1.1 after 4 months of oxaliplatin-based doublets or triplets with or without anti-VEGF or anti-EGFR agents
Availability of Formalin-Fixed Paraffin-Embedded tumor tissue
Treatment with Niraparib must be started after at least 2 weeks the end of platinum-based induction therapy up to 6 weeks
Eastern Cooperative Oncology Group Performance Status < 1
Adequate normal organ and marrow function as follow: Haemoglobin≥9.0 g/dL; b. Absolute neutrophil count ≥1.5 × 109 /L; Platelet count ≥100 × 109/L; Serum bilirubin ≤1.5 x Upper Limit of Normal This will not apply to patients with Gilbert's syndrome; Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula; Aspartate aminotransferase /Alanine Aminotransferase ≤2.5 x Upper Limit of Normal o ≤ 5 x Upper Limit of Normal in the presence of liver metastases
Willing and able to comply with all of the requirements and visits in the protocol
Participant must agree not to donate blood during the study or for 90 days after the last dose of Niraparib
Fertile women must have a negative urine or serum pregnancy test within 7 days prior to taking study treatment
Fertile women must use highly effective contraception, starting with the screening visit through 6 months post last dose of Niraparib.
Male participant agrees to use an adequate method of contraception starting with the first dose of study treatment through 90 days after the last dose of study treatment.
Male participant must not donate sperm for 90 days after last dose of Niraparib.

Exclusion criteria

Prior adjuvant treatment for stage II/III colorectal cancer ending within 12 months before the start of induction treatment
Patients with Microsatellite instability high or DNA mismatch repair deficiency DSBs DNA double-strand breaks are not allowed
Any systemic disease that, in the opinion of the Investigator, it is not compatible with the protocol
Major surgery ≤ 3 weeks prior to initiating Niraparib
Participation in another interventional clinical trial
Radiation therapy encompassing >20% of the bone marrow within 2 weeks; or any radiation therapy < 1 week prior to taking Niraparib
Hypersensitivity to Niraparib components or excipients
Transfusion (platelets or red blood cells) ≤ 4 weeks prior to initiating Niraparib
Colony stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior Niraparib
Any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted > 4 weeks
History of myelodysplastic syndrome, acute myeloid leukemia or Prior Reversible Encephalopathy Syndrome
Serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection.
Diagnosis, detection, or treatment of another type of cancer ≤ 2 years prior to initiating Niraparib (except basal or squamous cell carcinoma of the skin and cervical cancer in situ that has been definitively treated)
Active infection with Human Hepatitis B Virus or Hepatitis C Virus
Pregnancy or breastfeeding
Any impairment of gastrointestinal function or disease that may significantly impair the absorption of oral drugs, malabsorption syndrome, bowel obstruction, or inability to swallow tablets).