Phase I/II Study of BGB-290 with Temozolomide in Recurrent Gliomas with IDH1/2 Mutations (ABTC-1801)
Johns Hopkins Kimmel Cancer Center in Baltimore
Determine the safety and tolerability of the combination of pamiparib (BGB-290) and the temozolomide (TMZ) in patients with recurrent IDH1/2 mutant glioma. Determine the overall response rate of pamiparib (BGB-290) with TMZ in patients with recurrent IDH1/2-mutant gliomas that progressed on TMZ and another alkylator.
1. Phase I patients must have histologically confirmed WHO grade II-III glioma that is progressive or recurrent following at least one prior chemoradiation regimen. Phase I patients may have failed an unlimited number of prior systemic regimens. Phase II patients must have histologically confirmed WHO grade II-IV glioma that is progressive or recurrent following therapy: Phase 1, Phase II & Surgical Portion: Recurrence in non-enhancing tumors will be defined as 25% or more increase in bi-dimensional product of FLAIR signal abnormality (measurable disease) per the low-grade glioma (LGG) RANO criteria. Contrast-enhancing tumors with measurable enhancing targets will be defined as recurrent based on standard RANO criteria. Please refer to the Imaging Core Manual for further imaging requirements and submission information. Patients with recurrent glioma less than 12 weeks after completion of radiotherapy must have new enhancement outside of the RT field (beyond the high-dose region or 80% isodose line), or evidence of viable tumor on histopathologic sampling. Arm A patients must have WHO grade II-III glioma and have failed TMZ and another alkylator (e.g., carmustine, lomustine, procarbazine). Patients in Arm A may have failed an unlimited number of prior systemic regimens. Prior radiotherapy (RT) is not required for eligibility. Arm B patients must have WHO grade II-III glioma and have experienced tumor progression after TMZ or another alkylator (maximum one prior chemotherapy regimen), and have gone equal to 12 months since last treatment (chemotherapy or RT). Prior RT is allowed but not mandated. GBM Arm patients must have WHO grade IV glioblastoma following radiotherapy (45-60 Gy in 1.8-2.0 Gy fractions) plus chemotherapy and may have failed an unlimited number of prior systemic regimens. 2. Surgical Portion patients must have histologically confirmed WHO grade II-IV glioma that is progressive or recurrent following therapy and must be undergoing repeat surgery that is clinically indicated as determined by their care providers. Surgical Portion patients may have had an unlimited number of prior therapy regimens. 3. Phase I and Phase II patients must have available at least 3 prior full sets of MRI scans (not including screening), each separated by at least 2 months. Sites must agree to provide MRI Imaging form within four weeks after treatment start. Please refer to the Imaging Core Manual for further imaging requirements and submission information. 4. Patients must have IDH1/2-mutant glioma. IDH1/2-mutation status can be confirmed by immunohistochemistry (IHC) or direct DNA sequencing, provided that it is performed in a CLIA/CAP-certified laboratory. IDH1/2 mutations must be associated with neomorphic activity of the encoded proteins (i.e. IDH1 R132, IDH2 R172, IDH2 R140, IDH1 R100, IDH1 G97, IDH1 Y13929). 5. Patients must have archival FFPE specimens and mutations will be verified centrally, although this will not preclude patients with appropriate documentation of IDH1/2-mutant status from trial enrollment. Patients must have a tumor tissue form indicating availability of archived tissue from a previous surgery, completed and signed by a pathologist; sites must agree to provide this form within 14 days after treatment start. 6. Patients must have measurable (defined by at least 1 cm x 1 cm) contrast-enhancing disease or measurable abnormal T2/FLAIR hyper-intensity indicative of tumor by MRI imaging within 21 days of starting treatment. Please refer to the Imaging Core Manual for further imaging requirements and submission information. 7. Patients must have documented molecular 1p/19q and MGMT status. If either of these studies has not been performed previously, they can be done prior to enrollment. 8. Patients must be able to undergo MRI of the brain with gadolinium. Patients must be maintained on a stable or decreasing dose of corticosteroid regimen (no increase for 5 days) prior to this baseline MRI. Please refer to the Imaging Core Manual for further imaging requirements and submission information. 9. Patients must have recovered ( less than CTCAE grade 2 or baseline) from severe toxicity of prior therapy. The following intervals from previous treatments are required to be eligible: 12 weeks from the completion of radiation; 6 weeks from a nitrosourea chemotherapy; 3 weeks from a non-nitrosourea chemotherapy; 4 weeks from any investigational (not FDA-approved) agents; 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g., erlotinib, hydroxychloroquine, etc.). 10. Patients must be 18 years of age or older. 10. Patients must have a Karnofsky Performance (KPS) Status ? 60% (i.e. the patient must be able to care for himself/herself with occasional help from others). 11. Patients must have the following organ and marrow function: Absolute neutrophil count greater than 1,500/ µL; Platelets greater than 100,000/ µL; Hemoglobin greater than 9 g/dL; Total bilirubin ? institutional upper limit of normal; AST (SGOT)/ALT (SGPT) ? 4 × institutional upper limit of normal; Creatinine equal to institutional upper limit of normal OR Creatinine clearance greater than 60 ml/min/1.73m2 for patients with creatinine levels above institutional normal; APTT or PTT equal to 1.5 × institutional upper limit of normal. 12. Patients must be able to provide written informed consent. 13. Women of childbearing potential must have a negative serum pregnancy test within 7 days of randomization. Women of childbearing potential and men must agree to use highly effective contraception (refer to Appendix III for more details) prior to study entry, for the duration of study participation, and through 6 months after the last dose of study drug. Patients should consult their physician regarding what contraceptive method should be used. It should be noted, however, that barrier contraception (including male and female condoms with or without spermicide) is not considered a highly effective method of birth control or pregnancy prevention and if used must be combined with a highly effective contraceptive method. Women of childbearing potential must also agree to monthly pregnancy tests. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study or within 6 months after completing the study treatment, she should inform her treating physician immediately. The study doctor will monitor the pregnancy at least up to completion and at most up to 8 weeks following the delivery date (refer to Monitoring Pregnancy Section for more details). In addition, women who become pregnant while participating in the study must immediately stop taking study treatment. Men treated or enrolled on this protocol must also agree to use condoms in addition to 1 of the highly effective methods of contraception (listed in Appendix III) prior to the study, for the duration of study participation, and through 6 months after completion of pamiparib (BGB-290) or temozolomide administration. Women and men should not donate and/or freeze egg/sperm while participating in the study and for at least 6 months after completing study treatment. If a woman or man is in an exclusive same-sex relationship and is not engaged in attempts to become pregnant or father a child, it is not necessary to use a highly effective contraceptive method. 14. Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder. Patients with prior malignancies must be disease-free for ? 5 years. 15. Patients must be able to swallow tablets and capsules.
Phase 1- Single dose level of pamiparib (BGB-290) will be tested in combination with flat-dosing of TMZ. Pamiparib (BGB-290) will be administered orally, in capsule formation, at 60mg PO BID. The first dose level is 20mg QD days 1-28, every 28 days. Pamiparib (BGB-290) will be given orally twice daily on days 1 to 28 of 28-day cycles. TMZ will be given orally once daily on treatment days as defined per dose level. Patients will be followed by routine blood work, general and neurological examination, and MR imaging. Patients may continue to receive cycles of pamiparib (BGB-290) until tumor progression. Phase 2- Arm A: 15 patients will be enrolled. This arm of the trial will be stopped if no response is obtained among the first 15 patients. Otherwise, the study will continue and 10 additional patients will be enrolled. Pamiparib (BGB-290) will be given orally twice daily at 60mg PO BID on Days 1 to 28 of 28-day cycles. Patients will be followed by routine blood work, general and neurological examination, and MR imaging. Arm B: 24 patients will be enrolled into Arm B. This arm of the trial will be stopped if 7 or fewer responses are obtained among the first 24 patients ( equal to 7/24). Otherwise, the study will continue and 29 additional patients will be enrolled into Arm B. Pamiparib (BGB-290) will be given orally twice daily at 60mg PO BID on Days 1 to 28 of 28-day cycles. Patients will be followed by routine blood work, general and neurological examination, and MR imaging.
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