Patient case: 54-year-old male with malignant hyperthermia; genetic feature: RYR1

Clinical trial: The Safety, Pharmacokinetics and Antitumor Activity of BGB-A317 in Combination With BGB-290 in Subjects With Advanced Solid Tumors

Summary: The Safety, Pharmacokinetics and Antitumor Activity of the Anti-PD-1 Monoclonal Antibody BGB-A317 in Combination With the PARP Inhibitor BGB-290 in Subjects With Advanced Solid Tumors


Eligibility: Inclusion Criteria:
  1. Patients have voluntarily agreed to participate by giving written informed consent.
  2. Patients must have received standard of care in the primary treatment of their disease.
  3. Patients who have the below specified histologically confirmed malignancies that have progressed to the advanced or metastatic stage.
  1. In Part A, the patients must have an advanced malignancy including but not limited to high-grade serous cancer of the ovary, fallopian tube, or peritoneum, triple negative breast cancer, SCLC, primary peritoneal cancer, and any tumor likely to harbor DNA damage repair deficiencies susceptible to treatment with a PARP inhibitor or likely to be responsive to a PD-1 blocker.
  2. In Part B, the patients recruited to one of the eight expansion arms must have advanced solid tumors of the following types:
  Arm 1: Patients with relapsed, platinum-sensitive high grade epithelial, non-mucinous, ovarian cancer, fallopian tube, or primary peritoneal cancer (EOC) must meet the following criteria:
  i. Patients must have at least 2 prior platinum-containing treatments in any treatment setting.
  • Note: patients may have received additional therapy after the last platinum-containing regimen if the other eligibility criteria are met.
  ii. Patients must have platinum-sensitive recurrent disease and must not have progressed (by RECIST v1.1 criteria) within 6 months of the completion of the last platinum containing line of treatment
  • Note: patients may receive additional non-platinum based chemotherapy for recurrence after prior last platinum containing regimen if the criteria for platinum sensitivity are met.
  iii. Arm 1a: Patients with relapsed, platinum-sensitive high grade epithelial, non-mucinous, ovarian cancer, fallopian tube, or primary peritoneal cancer (EOC) with either known deleterious or suspected deleterious germline or somatic BRCA1/2 mutations or with HRD
  • If HRD or BRCA1/2 mutation status from archival tissue is unknown or has not been previously evaluated, then the archival tissue must undergo tissue screening using a validated diagnostic test to determine eligibility. If the diagnostic test result is BRCA1/2 or HRD positive the patient will be eligible for enrollment in Arm 1a iv. Arm 1b: Patients with relapsed, platinum-sensitive high grade EOC who otherwise meet the above criteria and are without known germline or somatic BRCA1/2 mutations and without HRD mutation
  Arm 2: Patients with triple negative breast cancer must meet the following criteria:
  i. Patients with 0-1 prior platinum-containing treatment in any treatment setting
  • Note: patients could have received additional therapy after the last platinum-containing line of treatment if the other eligibility criteria are met.
  ii. Patients who have received at least 1 prior treatment but not more than 3 prior lines of treatment in the advanced or metastatic setting.
  iii. Known deleterious or suspected deleterious germline or somatic BRCA1/2 mutations or with documented HRD
  -  If HRD or BRCA1/2 mutation status from archival tissue is unknown or has not been previously evaluated, then the archival tissue must undergo tissue screening using a validated diagnostic test to determine eligibility. If the diagnostic test result is HRD positive, then the patient will be eligible for enrollment in Arm 2
  -  If archival tissue is not available and the patient submits a fresh tumor biopsy, then the diagnostic test needs to demonstrate somatic BRCA1/2 mutation or HRD positivity.
  Arm 3: Patients with metastatic castration-resistant prostate cancer, including but not limited to mutations in homologous recombination (HR) pathways and/or defined by HRD algorithms, and must meet the following criteria:
  i. The patient may be either chemotherapy-naïve, but must have received prior abiraterone acetate and/or enzalutamide treatment, or have previously had no more than 2 taxane-based chemotherapy lines of treatment including docetaxel and carbazitaxel. If docetaxel is used more than once, this will be considered as 1 line of treatment.
  ii. At least 2 weeks since the completion of prior flutamide, bicalutamide, and nilutimide, or enzalutamide and abiraterone treatment.
  iii. Documented prostate cancer with one of the following:
  -  Surgically or medically castrated. The testosterone levels do not need to be checked if the patient has undergone surgical castration for > 4 months. Patients receiving chemical castration should have testosterone levels checked at baseline and confirmed to be in the castrate levels (< 0.5 ng/mL or 1.735 nM). In all cases the luteinizing hormone-releasing hormone (LHRH) antagonist/agonist is to be continued in these patients
  -  Patients with only non-measurable bone lesions must have disease progression based on PCWG3 with 2 or more new lesions or have prostate-specific antigen (PSA) progression before enrolment iv. Known deleterious or suspected deleterious germline or somatic BRCA1/2 mutations or with documented HRD
  -  If HRD or BRCA1/2 mutation status from archival tissue is unknown or has not been previously evaluated, then the archival tissue must undergo tissue screening using a validated diagnostic test to determine eligibility. If the diagnostic test result is HRD positive, then the patient will be eligible for enrollment in Arm 3
  -  If archival tissue is not available and the patient submits a fresh tumor biopsy, then the diagnostic test needs to demonstrate somatic BRCA1/2 mutation or HRD positivity.
  Arm 4: Patients with extensive-stage disease small cell lung cancer (SCLC) must meet the following criterion:
  i. Patients received at least 1 and not more than 2 prior lines of treatment ii. At least 1 prior line of treatment must have contained a platinum agent
  Arm 5: Patients with HER2-negative gastric or gastroesophageal junction cancer must meet the following criteria:
  i. Patients with HER2-negative may have received at least 1 and not more than 2 prior lines of treatment
  Arm 6: Patients with locally advanced or metastatic urothelial (muscle-invasive bladder, ureter, urethra or renal pelvis) cancer must meet the following criteria:
  i. Patients received at least 1 and not more than 2 prior lines of treatment in the advanced or metastatic disease setting ii. At least 1 prior line of treatment must have contained a platinum agent
  Arm 7: Patients with advanced or metastatic pancreatic adenocarcinoma must meet the following criteria:
  i. Received at least one but not more than 2 lines of treatment in either an advanced or metastatic setting; ii. At least 1 prior treatment for advanced or metastatic disease must have contained a platinum agent iii. Patients with known deleterious germline or somatic BRCA1/2 mutation can be considered for the study even if platinum-naive
  Arm 8: (NOTE: CLOSED TO ENROLLMENT) Patients with advanced or metastatic recurrent non-ovarian gynecological cancers (endometrial cancer, cancer of the cervix and patients with tumors known to be MMR deficient or HRD positive) must meet the following criteria:
  i. Patients with a complete response, partial response or stable disease from at least 1 prior platinum-containing treatment in any treatment setting.
  ii. The Sponsor medical monitor will approve tumor types for Arm 8 prior to screening
  • Note: Excluded tumor types include patients with bone or soft tissue sarcoma; central nervous system (CNS) malignancies; colorectal cancer (except microsatellite instability-high [MSI H] colorectal cancer is permitted); cutaneous or ocular melanoma; hematologic malignancies; HER2-negative breast cancer without BRCA mutation; mesothelioma, papillary, follicular, medullary or Hürthle cell thyroid cancer; unknown primary malignancy
  4. Patients who were treated with chemotherapy or any investigational therapies, if eligible, must have been completed at least 4 weeks or at least 5 half-lives (whichever is longer, but no less than 3 weeks) before the study drug administration, and all AEs have either returned to baseline or
  5. At least 2 weeks from palliative radiotherapy
  6. Patients must have archival tumor tissue or agree to a tumor biopsy for mutation and biomarkers analysis unless previously discussed with sponsor's medical monitor or its designee (fresh tumor biopsies are recommended at baseline in patients with readily accessible tumor lesions and who consent to the biopsies). Patients with ovarian, fallopian tube, primary peritoneal, or breast cancer in Part A and all patients enrolled in Part B must also agree to provide fresh blood sample at the baseline for the evaluation of BRCA mutations and/or confirmation of prior BRCA results or other homologous recombination deficiency mutations even if it was previously tested
  7. Patients must have measurable disease as defined in RECIST v1.1. Patients with metastatic castration-resistant prostate cancer and epithelial, non-mucinous, ovarian cancer, fallopian tube, or primary peritoneal cancer may use separate disease-specific criteria
  8. Patients must be a male or female ≥ 18 years of age on the day of signing informed consent
  9. Patients must have an ECOG Performance Status (PS) ≤ 1
  10. Patients must have a life expectancy ≥ 12 weeks
  11. Patient must have adequate organ function
  12. Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study, and for at least 6 months after the last dose of investigational drug, and have a negative serum pregnancy test within 7 days of the first dose of study drug(s)
  13. Non-sterile males and their female partners must be willing to use a highly effective method of birth control for the duration of the study and for at least 6 months after the last dose of investigational drug. Nonsterile males must avoid sperm donation for the duration of the study and for at least 6 months after last study drug
  14. Female patient must agree not to breastfeed starting at screening and throughout the study period, and for 6 months after the final study drug administration
  Exclusion criteria:
  1. Platinum-resistant/refractory disease, defined as progressive disease at the first tumor assessment while receiving platinum-containing chemotherapy
  2. Patient has history of severe hypersensitivity reactions to other monoclonal antibodies (mAbs).
  3. Any major surgery within 28 days before first dose of study drugs.
  4. Prior allogeneic stem cell transplantation or organ transplantation.
  5. Patients with toxicities (as a result of prior anticancer therapy) which have not recovered to baseline or stabilized, except for AEs not considered a likely safety risk (eg, alopecia, neuropathy and specific laboratory abnormalities).
  6. Concurrent participation in another therapeutic clinical trial.
  7. Prior malignancy within the previous 2 years except for locally curable non-melanoma dermatologic cancers that have been apparently cured, such as basal or squamous cell skin cancer, or carcinoma in situ of the skin, cervix, breast, bladder, or prostate.
  8. Symptomatic CNS metastasis or leptomeningeal disease. Note: Baseline MRI of the brain and spinal cord is required for SCLC patients enrolled in Arm 4 if they have a history of CNS disease.
  Note: Patients with previously treated CNS metastatic disease are eligible for any arm if CNS metastatic disease is asymptomatic, clinically stable, and does not require corticosteroids or anticonvulsants within a minimum of 4 weeks of enrollment.
  9. Prior therapies targeting PD-1, programmed death-ligand 1 (PD-L1), or PARP. The exception to this criterion are patients eligible for Arm 9; where patients may have received either a PD-1 inhibitor or PD-L1 inhibitor.
  10. Active autoimmune diseases or history of autoimmune diseases that may relapse.
  Note: Patients with the following diseases are not excluded and may proceed to further screening:
  1. Controlled Type I diabetes.
  2. Hypothyroidism managed with no treatment other than with hormone replacement therapy.
  3. Controlled celiac disease.
  4. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia).
  5. Any other disease that is not expected to recur in the absence of external triggering factors.
  11. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication within 2 weeks of the study drug administration.
  Note: Patients who are currently or have previously been on any of the following steroid regimens are not excluded:
  1. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent).
  2. Topical, ocular, intra-articular, intranasal, or inhalational corticosteroid with minimal systemic absorption.
  3. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type hypersensitivity reaction caused by contact allergen).
  12. With severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy, including tuberculosis infection, etc.
  13. History of interstitial lung disease, non-infectious pneumonitis or uncontrolled systemic diseases, including diabetes, hypertension, pulmonary fibrosis, acute lung diseases, etc.
  14. History of non-viral hepatitis or cirrhosis.
  15. Positive human immunodeficiency virus (HIV) status.
  16. A known history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
  17. History of alcohol abuse.
  18. Underlying medical conditions or alcohol or drug abuse or dependence that, in the investigator's opinion, will be unfavorable for the administration of study drug or affect the explanation of drug toxicity or adverse events; or insufficient compliance during the study according to investigator's judgement.
  19. Inability to swallow oral medications (capsules and tablets) without chewing, breaking, crushing, opening or otherwise altering the product formulation. Patients should not have gastrointestinal illnesses that would preclude the absorption of pamiparib, which is an oral agent.
  20. Has been administered a live vaccine within 4 weeks (28 days) of initiation of study therapy.
  21. Any of the following cardiovascular criteria:
  1. Current evidence of cardiac ischemia.
  2. Current symptomatic pulmonary embolism.
  3. Acute myocardial infarction ≤ 6 months prior to Day 1.
  4. Heart failure of New York Heart Association Classification III or IV ≤ 6 months prior to Day 1.
  5. Grade ≥ 2 ventricular arrhythmia ≤ 6 months prior to Day 1.
  6. History of cerebrovascular accident within 6 months before first dose of study drugs.
  22. Use or have anticipated need for food or drugs known to be strong or moderate cytochrome P450 (CYP)3A inhibitors or strong CYP3A inducers ≤ 10 days (or ≤ 5 half-lives, whichever is shorter) prior to Day 1

Relevance to patient case: not relevant