BGB-290-103 A Phase 1b Study of BGB-290
Research type
Research Study
Full title
A Phase 1b Study to Assess the Safety, Tolerability, and Clinical Activity of BGB-290 in Combination with Temozolomide (TMZ) in Subjects with Locally Advanced or Metastatic Solid Tumors
IRAS ID
236272
Contact name
Ruth Plummer
Contact email
Sponsor organisation
BeiGene USA, Inc.
Eudract number
2017-001553-14
Duration of Study in the UK
2 years, 3 months, 16 days
Research summary
Research summary- This is an open-label, multi-centre Phase 1b study to determine the safety and tolerability of BGB-290 when given orally in combination with temozolomide (TMZ) (pulsed and continuous), to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) for BGB-290 combined with TMZ (pulsed and continuous) and to select the recommended Phase 2 dose and schedule of BGB-290 in combination with TMZ. The second phase (dose expansion) of the study which is the phase we will be conducting in the UK will further evaluate the safety and anti-tumor activity of BGB-290 in combination with TMZ at the dose and schedule that will be chosen based on all data available from the dose escalation phase. Five different solid malignancy types will be evaluated in cohorts of approximately 20 subjects each. Enrollment into these cohorts will occur simultaneously and independent of each other. Five (5) different groups of approximately 20 patients each will be assigned, based on their type of cancer, to receive the selected schedule and dose of BGB-290 and TMZ on a 28-day treatment cycle.
Summary of results- Researchers look at the results of many studies to decide if a study treatment works, how it works, and if it is safe for patients. It takes people taking part in many studies around the world to help researchers make these decisions. This summary only shows the results from this study. Other studies might have different results.
Sponsor: BeiGene, Ltd.
Medicine(s) Studied: Pamiparib (BGB-290) Protocol Number: BGB-290-103 Dates of Study: July 2017 to May 2023 Title of This Study: A Phase 1b Study of Pamiparib (BGB-290) in Combination with Temozolomide (TMZ) in Subjects with Locally Advanced or Metastatic Solid Tumors Date of This Report: July 2023 THANK YOU!
Beigene, who managed this study, thanks the study patients for taking part in the clinical study for a new combination treatment of pamiparib (BGB-290) and temozolomide (TMZ, a type of chemotherapy) to treat patients with locally advanced or metastatic solid tumors. These included ovarian cancer, breast cancer, lung cancer, gastric/gastroesophageal junction cancer and other solid tumors with positive homologous recombination deficiency status.
Beigene thinks it is important to share the results of the study with the public. If you participated in the study and have questions about the results, please speak with the doctor or staff at your study center.
Why was this study done?
Clinical trials have investigated TMZ in combination with PARP inhibitors for a variety of malignancies and efficacy improvements have been observed. However, hematological toxicities were commonly reported as with PARP inhibitor monotherapy.
Pamiparib is a potent, selective PARP inhibitor that has been approved in China, which works by blocking DNA damage repairing to cause the cancer cell death.
Researchers initially conducted a phase 1a (also called dose-escalation) study to investigate a series of TMZ dosing regimens to determine the maximum tolerated dose and recommended phase 2 dose of TMZ in combination with pamiparib. The following phase 1b (also called dose expansion) study was done to assess the safety, tolerability as well as clinical activity of pamiparib in combination with TMZ in patients with various solid tumors that spread locally or to other organs (metastasized).
Researchers in this study mainly wanted to know:
• Whether pamiparib in combination with TMZ is safe and tolerable in patients and what is the maximum dose that can be tolerated or administered
• The recommended dose for phase 2 study
• Is there any antitumor activity of pamiparib in combination with TMZ
Who was in this study?
A total of 139 patients had solid tumors that spread locally or to other organs (metastasized), 66 patients in dose escalation stage and 73 patients in dose expansion stage. The expansion cohort enrolled patients with ovarian cancer, triple-negative breast cancer, small cell lung cancer or other homologous recombination deficiency positive tumor types.Dose escalation stage
Dose expansion stage
When and where was this study done?
This study started in July 2017 and ended in May 2023. The study was conducted at multiple study centers in countries worldwide, including the United States, United Kingdom, Spain and Australia.
How was this study done?
The study included two stages, a dose-escalation stage and a dose-expansion stage. The dose-escalation stage had a modified 3+3 design with a fixed dose of pamiparib in combination with escalating doses of TMZ in either pulsed or continuous administration.
During the dose-expansion stage, six dose-expansion cohorts of various tumor types were planned based on indication and/or homologous recombination deficiency status. Pamiparib was administered continuously in combination with TMZ at the dose and schedule determined in the dose-escalation phase. Each cohort was evaluated independently and could be closed due to lack of enrollment, antitumor activity, or other reasons.
What adverse events did patients have?
Adverse events are unwanted medical problems that may or may not be caused by the study treatment. An adverse event is called “serious” if it causes long-lasting problems, puts the patient in the hospital, is life-threatening, is considered “medically important” by the study doctor, or leads to death.
In the dose escalation stage, a total of 66 patients were evaluated for adverse events. All patients had at least one adverse event and 57 (86.4%) experienced an adverse event considered to be related to pamiparib or TMZ. Fifty patients (75.8%) experienced grade 3 or higher adverse events. Twenty patients (30.3%) had serious adverse events, and four patients (6.1%) had adverse events that caused them to stop treatment.
In the dose expansion stage, a total of 73 patients were evaluated for adverse events. 71 patients (97.3%) had at least one adverse event and 66 (90.4%) experienced an adverse event considered to be related to pamiparib or TMZ. Fifty-five patients (75.3%) experienced a grade 3 or higher adverse events. Thirty patients (41.1%) had serious adverse events, and six patients (8.2%) had adverse events that caused them to stop treatment.
What grade 3 or higher adverse events did patients have?
In the dose escalation stage, the most common grade 3 or higher adverse events were anemia (23 patients, 34.8%), neutropenia (18 patients, 27.3%), and thrombocytopenia (13 patients, 19.7%), and neutrophil count decreased (11 patients, 16.7%).
In the dose expansion stage, the most common grade 3 or higher adverse events were anemia (26 patients, 35.6%), neutropenia (16 patients, 21.9%), and neutrophil count decreased (15 patients, 20.5%), and thrombocytopenia (13 patients, 17.8%).
What serious adverse events did patients have?
In the dose escalation stage, the most common of serious adverse events were abdominal pain (3 patients, 4.5%) and pneumonia (2 patients, 3.0%).
In the dose expansion stage, the most common of which were anemia (4 patients, 5.5%), abdominal pain (3 patients, 4.1%), neutropenia (3 patients, 4.1%), and thrombocytopenia (3 patients, 4.1%).
What were the most common adverse events?
In the dose escalation stage, the most common adverse events were anemia (37 patients, 56.1%), nausea (36 patients, 54.5%), and fatigue (32 patients, 48.5%). These were also the most common adverse events related to either pamiparib or TMZ (anemia: 36 patients, 54.5%; nausea: 27 patients, 40.9%; fatigue: 25 patients, 37.9%).
In the dose expansion stage, the most common adverse events were anemia (46 patients, 63.0%), nausea (36 patients, 49.3%), and fatigue (35 patients, 47.9%). These were also the most common adverse events related to either pamiparib or TMZ (anemia: 43 patients, 58.9%; nausea: 31 patients, 42.5%; fatigue: 25 patients, 34.2%).
What is the maximum dose that can be administered and what is the recommended dose for phase 2 study?
The maximum dose that be administered in patients was 60 mg pamiparib twice a day with 7-day pulsed TMZ 60 mg once a day or continuous TMZ 20 mg once a day. The recommended dose for phase 2 study administered in the dose expansion stage was 60 mg pamiparib twice a day with 7-day pulsed TMZ 60 mg once a day.
Is there any antitumor activity of pamiparib in combination with TMZ?
The proportion of patients with response to treatment completely or partially is called “Object Response Rate”. ORR was the most important parameter to estimate the antitumor activity of the study drugs in this study.
In the dose escalation stage, the confirmed ORR for patients who were efficacy-evaluable was 13.8%. No patients experienced confirmed complete response, eight patients (13.8%) achieved partial response, and 29 patients (50.0%) had stable disease.
In the dose expanse stage, the confirmed ORR for patients who were efficacy-evaluable was 11.6%. One patient (1.4%) with leiomyosarcoma that was homologous recombination deficiency positive and had a germline BRCA2 mutation experienced confirmed complete response, seven patients (10.1%) achieved partial response, and 32 patients (46.4%) had stable disease.
The confirmed ORR for both the dose-escalation and -expansion stages combined was 12.6% (16/127 patients).
What were the main results of the study?
This study demonstrated that the combination of pamiparib and TMZ shows some potential clinical benefit, especially in patients with certain homologous recombination deficiency positive tumor types, which needs to be confirmed in studies enrolling more patients. Treatment with 60 mg pamiparib in combination with low doses of TMZ was generally well tolerated in patients with solid tumors which spread locally or to other organs.
The safety profile of the combination of pamiparib with TMZ was consistent with the known risks of each study treatment component, demonstrating a comparable safety and tolerability profile in patients with locally advanced or metastatic solid tumors. No new safety signal was identified.
How has this study helped people?
The results from this study will help researchers and patients learn more about the safety, tolerability, and clinical activity of pamiparib in combination with TMZ in patients with solid tumors that spread locally or to other parts of the body.
The results in this summary come from this one study. Other studies may show different results. If you participated in this study and have questions about the results, please speak to the doctor or staff at your study center. You should not make changes to your treatments based on the results of this study.REC name
North East - Newcastle & North Tyneside 1 Research Ethics Committee
REC reference
17/NE/0380
Date of REC Opinion
29 Jun 2018
REC opinion
Further Information Favourable Opinion