The Safety, Pharmacokinetics and Antitumor Activity of BGB-A317 in Combination With BGB-290 in Participants With Advanced Solid Tumors
Condition: Solid Tumors
MeSH terms: Neoplasms
Intervention: Tislelizumab; Pamiparib
Intervention MeSH terms: Tislelizumab; Pamiparib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 229.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Dose Escalation; Dose Expansion; BGB-A317; BGB-290; Tislelizumab; Pamiparib

Summary:

      This trial studied the safety, pharmacokinetics, and antitumor activity of the
      anti-programmed cell death 1 (PD-1) monoclonal antibody (mAb) BGB-A317 (tislelizumab) in
      combination with the poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor BGB-290
      (pamiparib) in participants with advanced solid tumors.
    

Eligibility criteria:

        Key Inclusion Criteria:

          1. Participants voluntarily agreed to participate by giving written informed consent.

          2. Must have received standard of care in the primary treatment of their disease.

          3. Participants who had the below specified histologically confirmed malignancies that
             had progressed to the advanced or metastatic stage:

               1. In Part A, the participants must have had an advanced malignancy, including but
                  not limited to high-grade serous cancer of the ovary, fallopian tube, or
                  peritoneum, triple negative breast cancer, small cell lung 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 participants recruited to 1 of the 8 expansion arms must have had
                  advanced solid tumors of the following types:

             Arm 1: Participants with relapsed, platinum-sensitive high-grade epithelial,
             non-mucinous, ovarian cancer, fallopian tube, or primary peritoneal cancer (EOC) must
             have met the following criteria:

             i. Must have had at least 2 prior platinum-containing treatments in any treatment
             setting.

             ii. Must have had platinum-sensitive recurrent disease and must not have progressed
             (by Response Evaluation Criteria in Solid Tumors [RECIST] v1.1 criteria) within 6
             months of the completion of the last platinum-containing line of treatment.

             • Note: Participants may have received additional non-platinum-based chemotherapy for
             recurrence after prior last platinum-containing regimen if the criteria for platinum
             sensitivity were met.

             iii. Arm 1a: Participants with relapsed, platinum-sensitive high-grade EOC with either
             known deleterious or suspected deleterious germline or somatic breast cancer
             susceptibility gene 1/2 (BRCA1/2) mutations or with homologous recombination
             deficiency (HRD).

             • If HRD or BRCA1/2 mutation status from archival tissue was unknown or had not been
             previously evaluated, then the archival tissue must have undergone tissue screening
             using a validated diagnostic test to determine eligibility. If the diagnostic test
             result was BRCA1/2 or HRD positive, the participant was eligible for enrollment in Arm
             1a.

             iv. Arm 1b: Participants with relapsed, platinum-sensitive high grade EOC who
             otherwise met the above criteria and were without known germline or somatic BRCA1/2
             mutations and without HRD mutation.

             Arm 2: Participants with triple negative breast cancer must have met the following
             criteria:

             i. 0-1 prior platinum-containing treatment in any treatment setting.

             • Note: participants could have received additional therapy after the last
             platinum-containing line of treatment if the other eligibility criteria were met.

             ii. Participants who 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 was unknown or had not been
             previously evaluated, then the archival tissue must have undergone tissue screening
             using a validated diagnostic test to determine eligibility. If the diagnostic test
             result was HRD positive, then the participant was eligible for enrollment in Arm 2.

             • If archival tissue was not available and the participant submitted a fresh tumor
             biopsy, then the diagnostic test needed to demonstrate somatic BRCA1/2 mutation or HRD
             positivity.

             Arm 3: Participants 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 have met the following criteria:

             i. 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
             was used more than once, this was 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 did not need to be
                  checked if the participant had undergone surgical castration for > 4 months.
                  Participants receiving chemical castration should have had 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
                  antagonist/agonist was to be continued in these participants.

               -  Participants with only non-measurable bone lesions must have had disease
                  progression based on Prostate Cancer Clinical Trials Working Group with 2 or more
                  new lesions or have had prostate-specific antigen 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 was unknown or had not
                  been previously evaluated, then the archival tissue must have undergone tissue
                  screening using a validated diagnostic test to determine eligibility. If the
                  diagnostic test result was HRD positive, then the participant was be eligible for
                  enrollment in Arm 3.

               -  If archival tissue was not available and the participant summitted a fresh tumor
                  biopsy, then the diagnostic test needed to demonstrate somatic BRCA1/2 mutation
                  or HRD positivity.

             Arm 4: Participants with extensive-stage disease SCLC must have met the following
             criteria:

             i. 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: Participants with human epidermal growth factor receptor-2 (HER2)-negative
             gastric or gastroesophageal junction cancer must have met the following criteria:

             i. May have received at least 1 and not more than 2 prior lines of treatment

             Arm 6: Participants with locally advanced or metastatic urothelial (muscle-invasive
             bladder, ureter, urethra, or renal pelvis) cancer must have met the following
             criteria:

             i. 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: Participants with advanced or metastatic pancreatic adenocarcinoma must have
             met the following criteria:

             i. Received at least 1 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. Participants with known deleterious
             germline or somatic BRCA1/2 mutation could be considered for the study even if
             platinum naïve.

             Arm 8: (Note: Closed to enrollment) Participants with advanced or metastatic recurrent
             non-ovarian gynecological cancers (endometrial cancer, cancer of the cervix and
             participants with tumors known to be mismatch repair deficient or HRD positive) must
             have met the following criteria:

             i. Participants 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 would approve tumor types for Arm 8 prior to screening.

             • Note: Excluded tumor types included participants with bone or soft tissue sarcoma;
             central nervous system (CNS) malignancies; colorectal cancer (except microsatellite
             instability-high 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. Participants who were treated with chemotherapy or any investigational therapies, if
             eligible, must have 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
             adverse events (AEs) had either returned to baseline or stabilized.

          5. At least 2 weeks from palliative radiotherapy.

          6. Participants must have had 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 were recommended at baseline in
             participants with readily accessible tumor lesions and who consented to the biopsies).
             Participants with ovarian, fallopian tube, primary peritoneal, or breast cancer in
             Part A and all participants enrolled in Part B must also have agreed to provide fresh
             blood sample at the baseline for the evaluation of BRCA mutations and/or confirmation
             of prior BRCA results or other HR deficiency mutations, even if it was previously
             tested.

          7. Participants must have had measurable disease as defined in RECIST v1.1. Participants
             with metastatic castration-resistant prostate cancer and epithelial, non-mucinous,
             ovarian cancer, fallopian tube, or primary peritoneal cancer may have used separate
             disease-specific criteria.

          8. Male or female ≥ 18 years of age on the day of signing informed consent.

          9. Must have had an Eastern Cooperative Oncology Group Performance Status ≤ 1.

         10. Must have had a life expectancy ≥ 12 weeks.

         11. Must have had adequate organ function.

         12. Females of childbearing potential must have been 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 had 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 have been 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 have avoided
             sperm donation for the duration of the study and for at least 6 months after last
             study drug.

         14. Females must have agreed not to breastfeed starting at screening and throughout the
             study period, and for 6 months after the final study drug administration.

        Key Exclusion Criteria:

          1. Participants with ovarian cancer who have platinum-resistant/refractory disease,
             defined as progressive disease at the first tumor assessment while receiving
             platinum-containing chemotherapy.

          2. Participant had history of severe hypersensitivity reactions to other mAbs.

          3. Any major surgery within 28 days before first dose of study drugs.

          4. Prior allogeneic stem cell transplantation or organ transplantation.

          5. Participants with toxicities (as a result of prior anticancer therapy) that had not
             recovered to baseline or stabilized, except for AEs not considered a likely safety
             risk (for example, alopecia, neuropathy and specific laboratory abnormalities).

          6. Concurrent participation in another clinical trial.

          7. Prior malignancy within the previous 2 years except for locally curable non-melanoma
             dermatologic cancers that had 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 magnetic
             resonance imaging of the brain and spinal cord was required for SCLC participants
             enrolled in Arm 4 if they had a history of CNS disease.

             Note: Participants with previously treated CNS metastatic disease were eligible for
             any arm if CNS metastatic disease was asymptomatic, clinically stable, and did 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.

         10. Active autoimmune diseases or history of autoimmune diseases that may have relapsed.

             Note: Participants with the following diseases were not excluded and may have
             proceeded 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 (for example, vitiligo, psoriasis,
                  alopecia);

               5. Any other disease that was 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: Participants who were currently or had previously been on any of the following
             steroid regimens were 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 (for
                  example, for contrast dye allergy) or for the treatment of a non-autoimmune
                  condition (for example, 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, et cetera.

         13. History of interstitial lung disease, non-infectious pneumonitis or uncontrolled
             systemic diseases, including diabetes, hypertension, pulmonary fibrosis, acute lung
             diseases, et cetera.

         14. History of non-viral hepatitis or cirrhosis.

         15. Positive human immunodeficiency virus status.

         16. A known history of hepatitis B virus or hepatitis C virus infection.

         17. History of alcohol abuse.

         18. Underlying medical conditions or alcohol or drug abuse or dependence that, in the
             investigator's opinion, would be unfavorable for the administration of study drug or
             affect the explanation of drug toxicity or AEs; 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.
             Participants should not have had gastrointestinal illnesses that would have precluded
             the absorption of pamiparib, which was an oral agent.

         20. Had 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 had 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.

        Note: Other protocol-defined Inclusion/Exclusion criteria may have applied.