Niraparib Combined With Anlotinib in Homologous Recombination Repair (HRR) Gene-mutated Advanced Solid Tumors

• ClinicalTrials.gov Identifier: NCT04764084
• Recruitment Status: Not yet recruiting
• First Posted: February 21, 2021
• Last Update Posted: February 21, 2021
• Sponsor: Beijing Cancer Hospital
• Information provided by (Responsible Party): Li Huiping, Beijing Cancer Hospital

Study Description

Brief Summary:

Homologous Recombination Repair (HRR) gene mutations can be detected in many solid tumors, patients with HRR gene mutations may benefit from PARP inhibitor. Antiangiogenic drugs can induce hypoxia and increase the sensitivity to PARP inhibitor. The combination of PARP inhibitor and antiangiogenic drug can play a synergistic anti-tumor role and achieve good efficacy in HRR gene-mutated tumors. The purpose of the study is to determine the dose limiting toxicity (DLT) and maximum tolerable dose (MTD) of Niraparib plus Anlotinib in HRR gene-mutated advanced solid tumors, and evaluate the safety and effectiveness of this combination therapy preliminarily.

Condition or disease	Intervention/treatment	Phase
HER2-negative Breast Cancer; Gastric Adenocarcinoma; Cholangiocarcinoma; Pancreatic Cancer	Drug: Niraparib; Drug: Anlotinib	Phase 1

Detailed Description:

This is a single-arm, single-center, phase I study to investigate the DLT and MDT, safety and efficacy of Niraparib combined with Anlotinib in the treatment of advanced solid tumors with HRR gene mutations. In this study, 52 histological or cytological diagnosis, previous treatment failure patients of HER2 negative breast cancer, cholangiocarcinoma, gastric adenocarcinoma and pancreatic cancer are included and receive Niraparib combined with Anlotinib. Patients are required to carry pathogenic or suspected pathogenic gBRCA or sBRCA mutations, or HRR gene mutations defined by the inclusion criteria. The study will be divided into two phase. The first phase will include 6-12 patients on a 21-day cycle to determine the DLT and MTD. In the second phase, 40 patients will be included to treated with Niraparib plus Anlotinib until disease progression or intolerable toxicity or withdrawal of the trial.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 52 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single Arm, Single Center, Phase I Trial of Niraparib Plus Anlotinib in Advanced Solid Tumors With Homologous Recombination Repair (HRR) Gene Mutations
• Estimated Study Start Date: April 1, 2021
• Estimated Primary Completion Date: November 1, 2021
• Estimated Study Completion Date: February 28, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment group; Niraparib-Anlotinib combination therapy	Drug: Niraparib; Niraparib 100mg or 200mg, PO, qd，d1-d21; Other Name: Zejula; Drug: Anlotinib; Anlotinib 12mg, PO, qd，d1-d14

Outcome Measures

Primary Outcome Measures :

1. Dose limiting toxicity (DLT) and maximum tolerated dose (MTD) [ Time Frame: 4 weeks ]

Secondary Outcome Measures :

1. The frequency and severity of adverse events [ Time Frame: Baseline through 1 year ]
   The frequency and severity of adverse events and toxicity based upon NCI CTCAE version 5.0 during subjects receiving the treatment
2. Objective Response Rate (ORR) [ Time Frame: at 6 months ]
   The ORR is a combination of CR (the target lesion completely disappeared over 4 weeks) and PR (Target lesions were reduced by more than 30% for more than 4 weeks).
3. Progression-free survival (PFS) [ Time Frame: at 6 months ]
   PFS is defined as the time from enrollment to first documentation of tumor progression, or to death due to any cause in the absence of previous documentation of objective tumor progression.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Subjects understand the trial process, sign informed consent, agree to participate in the study, and have the ability to follow the protocol;
• 18 ~ 70 years old
• HER2 negative breast cancer, cholangiocarcinoma, gastric adenocarcinoma and pancreatic cancer confirmed by histology or cytology meet any of the following conditions: first line treatment failure of HER2 negative breast cancer; first line treatment failure of cholangiocarcinoma; second line treatment failure of gastric adenocarcinoma; first line treatment failure of pancreatic cancer
• At least one measurable target lesion that meet RECIST 1.1 criteria
• Can provide paraffin-embedded tumor tissue samples or plasma samples for HRR gene detection
• Carry pathogenic or suspected pathogenic germline or somatic HRR gene mutations, HRR genes include BRCA1, BRCA2, ATM, ATR, BAP1, BRIP1, CHEK2, FANCA, PALB2 and RAD51, mutations in other HRR genes should be evaluated by researchers and the pathogenicity should be supported by published literature or clinical studies.
• ECOG physical status score is 0-1
• Life expectancy > 6 months
• Good organ function, including: Neutrophil count >= 1500 / μL; Platelets >= 100,000 / μL; Hemoglobin >= 10g / dL; Serum creatinine <= 1.5 times the upper limit of normal value, or creatinine clearance >= 60mL / min (calculated according to Cockcroft-Gault formula); Total bilirubin <= 1.5 times the upper limit of normal value or direct bilirubin <= 1.0 times the upper limit of normal value; AST and ALT <= 2.5 times the upper limit of normal value. When liver metastases are present, it must be <= 5 times the upper limit of normal value
• The toxic side effects of any previous chemotherapy have recovered to <= CTCAE level 1 or baseline levels, except for sensory neuropathy or hair loss with stable symptoms <= CTCAE level 2

Exclusion Criteria:

• People who are known to be allergic to Niraparib or Anlotinib (or active or inactive ingredients of drugs with similar chemical structure)
• Symptomatic, uncontrolled brain or pia mater metastases
• Underwent major surgery within 3 weeks before the study began or has not recovered after surgery
• Received palliative radiotherapy of > 20% bone marrow 1 week before enrollment
• Have invasive cancer other than ovarian cancer (except fully treated basal or squamous cell skin cancer) within 2 years before enrollment
• Patients with tumor invasion of large vessels
• Previous or currently diagnosed myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)
• Severe or uncontrolled diseases, including but not limited to: uncontrollable nausea and vomiting, inability to swallow or gastrointestinal diseases that may interfere with drug absorption and metabolism; active viral infections; mental illnesses that affect patients' signed informed consent History of bleeding tendency and thrombosis; history of severe cardiovascular disease
• Laboratory abnormalities: hyponatremia; hypokalemia; uncontrollable nail function abnormalities
• Receive platelet or red blood cell transfusions within 4 weeks
• Patients who are pregnant or nursing, or who plan to become pregnant during study treatment
• Have previously received any PARP inhibitor or Anlotinib treatment

Contacts and Locations

Contacts

Contact: Jiayang Zhang, M.D.; +86-010-88196380; jiayangzhang2015@qq.com

Contact: Anqiang Wang, M.D.; +86-010-88196970; wanganqiang0902@163.com

Locations

China, Beijing

Beijing Cancer Hospital

Beijing, Beijing, China, 100142

Contact: Huiping Li, M.D. +86-010-88196739 huipingli2012@hotmail.com

Contact: Jiafu Ji, M.D. +86-010-88122437 jijiafu@hsc.pku.edu.cn

Sponsors and Collaborators

Beijing Cancer Hospital

Investigators

• Principal Investigator: Huiping Li, M.D.; Beijing Cancer Hospital
• Principal Investigator: Jiafu Ji, M.D.; Beijing Cancer Hospital

More Information

• Responsible Party: Li Huiping, Department of Breast Oncology, Beijing Cancer Hospital
• ClinicalTrials.gov Identifier: NCT04764084
• Other Study ID Numbers: ZL-2306-912 ALTER-OC-02
• First Posted: February 21, 2021
• Last Update Posted: February 21, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Within six months after the trial complete, study protocol, informed consent form and clinical study report will be shared.
• Supporting Materials: Study Protocol; Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: Within six months after the trial complete
• Access Criteria: Publication

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Li Huiping, Beijing Cancer Hospital:

Niraprib; Anlotinib; Homologous Recombination Repair; breast cancer; gastric Adenocarcinoma; cholangiocarcinoma; pancreatic cancer

Additional relevant MeSH terms:

Adenocarcinoma; Pancreatic Neoplasms; Cholangiocarcinoma; Neoplasms by Site; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Digestive System Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Niraparib; Poly(ADP-ribose) Polymerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents