Clinical Trials /

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

NCT02660034

Description:

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

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Breast Carcinoma
  • Fallopian Tube Carcinoma
  • Gastric Carcinoma
  • Malignant Solid Tumor
  • Ovarian Carcinoma
  • Pancreatic Adenocarcinoma
  • Peritoneal Carcinoma
  • Small Cell Lung Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: The Safety, Pharmacokinetics and Antitumor Activity of BGB-A317 in Combination With BGB-290 in Subjects With Advanced Solid Tumors
  • Official Title: A Phase 1/1b, Open Label, Multiple Dose, Dose Escalation and Expansion Study to Investigate 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

Clinical Trial IDs

  • ORG STUDY ID: BGB-A317/BGB-290_Study_001
  • NCT ID: NCT02660034

Conditions

  • Solid Tumors

Interventions

DrugSynonymsArms
BGB-A317Phase 1A
BGB-290Phase 1A

Purpose

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

Trial Arms

NameTypeDescriptionInterventions
Phase 1AExperimentalApproximately 50 subjects for the dose escalation until maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) determination
  • BGB-290
Phase 1BExperimentalApproximately 180 subjects for expansion in eight selected arms with nine cohorts.
  • BGB-290

Eligibility Criteria

        Inclusion Criteria:

          1. Patients have voluntarily agreed to participate by giving written informed consent.

          2. Patients who have the below specified histologically or cytologically 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
                  (EOC), triple negative breast cancer (TNBC), 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 must meet the following
             criteria:

             i. Patients must have at least 2 prior platinum-containing treatments in any treatment
             setting.

             • Note: patients could 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 regimen.

             • Note: patients can receive additional non-platinum based chemotherapy for recurrence
             after the 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 DNA HRD

             • If HRD or BRCA1/2 mutation status is unknown or has not been previously evaluated,
             then the patient must undergo tissue screening using the Myriad myChoice® diagnostic
             test to determine eligibility.

             iv. Arm 1b: Patients with relapsed, platinum-sensitive high grade epithelial,
             non-mucinous, ovarian cancer, fallopian tube, or primary peritoneal cancer (EOC)
             without either known deleterious or suspected deleterious germline or somatic BRCA1/2
             mutations or without DNA HRD • If HRD or BRCA1/2 mutation status is unknown or has not
             been previously evaluated, then the patient must undergo tissue screening using the
             Myriad myChoice® diagnostic test to determine eligibility.

             Arm 2: Patients with triple negative breast cancer must meet the following criteria:

             i. Patients with either known deleterious or suspected deleterious germline or somatic
             BRCA1/2 mutations or with DNA HRD.

             • If HRD or BRCA1/2 mutation status is unknown or has not been previously evaluated,
             then the patient must undergo tissue screening using the Myriad myChoice® diagnostic
             test to determine eligibility.

             ii. Patients with 0-1 prior platinum-containing treatment in any treatment setting.

             • Note: patients could have received additional therapy after the last
             platinum-containing regimen if the other eligibility criteria are met.

             iii. Patients who have received ≤ 3 prior lines of therapy in the advanced or
             metastatic setting.

             Arm 3: Patients with metastatic castration-resistant prostate cancer, including but
             not limited to mutations in HR pathways and/or defined by HRD algorithms, and must
             meet the following criteria:

             i. Patients with either known deleterious or suspected deleterious germline or somatic
             BRCA1/2 mutations or with DNA HRD.

             • If HRD or BRCA1/2 mutation status is unknown or has not been previously evaluated,
             then the patient must undergo tissue screening using the Myriad myChoice® diagnostic
             test to determine eligibility.

             ii. 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
             two taxane-based chemotherapy regimens including docetaxel and carbazitaxel. If
             docetaxel is used more than once, this will be considered as one regimen.

             iii. At least 2 weeks since the completion of prior flutamide, bicalutamide, and
             nilutimide, or enzalutamide and abiraterone treatment.

             iv. At least 2 weeks from any radiotherapy, with the exception of a single fraction of
             radiotherapy for the purposes of palliation (confined to one field).

             v. Documented prostate cancer progression 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 enrollment.

             Arm 4: Patients with extensive-stage disease small cell lung cancer (SCLC) must meet
             the following criterion:

             i. Patients received ≤ 2 prior lines of therapy.

             Arm 5: Patients with HER2-negative gastric or gastroesophageal junction cancer must
             meet the following criterion:

             i. Patients received ≤ 2 prior lines of therapy.

             Arm 6: Patients with locally advanced or metastatic urothelial (muscle-invasive
             bladder, ureter, urethra or renal pelvis) cancer must meet the following criterion:

             i. Patients received ≤ 2 prior lines of therapy in the advanced or metastatic disease
             setting.

             ii. Patients must have received prior platinum-based systemic chemotherapy.

             Arm 7: Patients with advanced or metastatic pancreatic adenocarcinoma must meet the
             following criteria:

             i. Patients must have received at least one line of platinum containing regimens in
             either an advanced or metastatic setting, unless the patient has known deleterious
             germline or somatic BRCA1/2 mutation prior to being screened (in which case they can
             be considered for the study if the patient has never received platinum-containing
             regimen), AND ii. Patients received ≤ 1 prior lines of therapy in the advanced or
             metastatic disease setting.

             Arm 8: Patients with advanced or metastatic solid tumor malignancies must meet the
             following criterion:

             i. Patients with at least 1 prior platinum-containing treatment in any treatment
             setting.

          3. Patients who were treated with chemotherapy, radiotherapy, immunotherapy or any
             investigational therapies, if eligible, must have been completed at least 4 weeks or
             at least 5 half-lives (whichever is shorter, but no less than 3 weeks) before the
             study drug administration, and all AEs have either returned to baseline or stabilized.
             Prior therapies targeting PD-1, programmed death-ligand 1 (PD-L1), or PARP is
             exclusionary (See Exclusion Criterion 5).

          4. 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 reconstitution deficiency mutation even if it was previously tested.

          5. Patients must have measurable or evaluable disease as defined per the RECIST v1.1
             except patients with mCRPC.

          6. Patients must be a male or female ≥ 18 years of age on the day of signing informed
             consent.

          7. Patients must have an ECOG Performance Status (PS) ≤ 1.

          8. Patients must have a life expectancy ≥12 weeks.

          9. Patient must have adequate organ function as indicated by the following laboratory
             values independent of transfusion within 2 weeks:

               1. Absolute neutrophil count (ANC) ≥ 1,500/mL

               2. Platelets ≥ 100,000/mL

               3. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L

               4. Serum creatinine ≤ 1.5 × upper limit of normal (ULN)

               5. Serum total bilirubin ≤ 1.5 × ULN (On fractionation ≤ 90% of total bilirubin
                  should be unconjugated. Total bilirubin must be <4 X ULN for patients with
                  Gilbert's syndrome).

               6. Aspartate aminotransferase (serum glutamic oxaloacetic transaminase [SGOT]) and
                  alanine aminotransferase (serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 × ULN
                  or ≤ 5 × ULN for patients with liver metastases

               7. International normalized ratio (INR) ≤ 1.5 × ULN (≤ 2.5 × ULN if on
                  anticoagulants)

         10. Female patients are eligible to enter and participate in the study if they are of:

             a) Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
             including any female who: i. has had a hysterectomy ii. has had a bilateral
             oophorectomy iii. has had a bilateral salpingectomy iv. is post menopausal (total
             cessation of menses for ≥ 1 year) b) Childbearing potential, has a negative serum
             pregnancy test at screening (within 7 days of the first investigational product
             administration), is not breast feeding, and uses highly effective contraception before
             study entry and throughout the study until 90 days after the last investigational
             product administration. Adequate contraception as recommended by the Clinical Trial
             Facilitation Group (CTFG)

         11. Male patients are eligible to enter and participate in the study if they are
             vasectomized or agree to use of contraception during the study treatment period and
             for at least 90 days after the last dose investigational product.

        Exclusion Criteria:

          1. Platinum-resistant/refractory disease, defined as progressive disease at the first
             tumor assessment while receiving platinum-based chemotherapy or within 6 months after
             treatment (for patients in Part B; disease-specific expansion arms only).

          2. Patient has history of severe hypersensitivity reactions to other monoclonal
             antibodies (mAbs).

          3. Prior malignancy within the previous 2 years except for locally curable cancers that
             have been apparently cured, such as basal or squamous cell skin cancer, or carcinoma
             in situ of the cervix or breast or bladder.

          4. Symptomatic central nervous system (CNS) metastasis(es). Note: Baseline CT/MRI of the
             brain is required for SCLC patients enrolled in Arm 4. Patients with previously
             treated CNS metastasis(es) are eligible if the patients with previously treated CNS
             metastasis(es) are asymptomatic and radiographically/clinically stable and not
             requiring steroids within 4 weeks prior to first dose.

             Note: Non-SCLC patients without clinical signs or symptoms of CNS involvement are not
             required to have a computed tomography (CT)/magnetic resonance imaging (MRI) scan of
             the brain unless it is considered standard of care.

          5. Prior therapies targeting PD-1, programmed death-ligand 1 (PD-L1), or PARP.

          6. Patients with active autoimmune diseases or history of autoimmune diseases should be
             excluded; these include but are not limited to patients with a history of
             immune-related neurologic disease, multiple sclerosis, autoimmune (demyelinating)
             neuropathy, Guillain-Barre syndrome, myasthenia gravis, systemic lupus erythematous
             (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease, Crohn's
             ulcerative colitis, hepatitis, toxic epidermal necrolysis (TEN), Stevens-Johnson
             syndrome, or anti-phospholipid syndrome.

             Note: Patient are permitted to enroll if they have controlled celiac disease,
             vitiligo, eczema, psoriasis, controlled Type I diabetes mellitus, endocrine
             deficiencies (including hypothyroidism) managed with replacement hormones including
             low-dose (≤10 mg/day prednisone equivalents) corticosteroids. Patients with
             rheumatological autoimmune diseases that are frequently limited in severity such as
             rheumatoid arthritis and Sjogren's syndrome are permitted to enroll if they do not
             require treatment with a non-biologic or biologic disease modifying anti-rheumatic
             drug (DMARDs), e.g. cyclophosphamide or adalimumab. All patients with an autoimmune
             rheumatological disease require evaluation for severity and target organ involvement.

          7. Patients should be excluded if they have a condition requiring systemic treatment with
             either corticosteroids (> 10 mg daily prednisone equivalents) or other
             immunosuppressive medications within 2 weeks of the study drug administration.

             Note: Adrenal replacement doses ≤ 10 mg daily prednisone equivalents are permitted in
             the absence of active autoimmune disease; patients are permitted to use topical,
             ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal
             systemic absorption); a brief course of corticosteroids for prophylaxis (e.g.,
             contrast dye allergy) or for treatment of non-autoimmune conditions (e.g.,
             delayed-type hypersensitivity reaction caused by contact allergen) is permitted.

          8. Has history of interstitial lung disease or non-infectious pneumonitis except for
             those induced by radiation therapies.

          9. Positive human immunodeficiency virus (HIV) status.

         10. Active infection requiring therapy, positive tests for Hepatitis B surface antigen
             (HBsAg) and/or Hepatitis B core antibody (HBcAb) positive or Hepatitis C virus (HCV)
             antibody positive at screening must not be enrolled until further definite testing
             with Hepatitis B virus (HBV) DNA titers and HCV RNA tests can conclusively rule out
             presence of active infection.

         11. Underlying medical conditions that, in the investigator's opinion, will make the
             administration of study drug hazardous or obscure the interpretation of toxicity
             determination or adverse events (AEs).

         12. 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
             BGB-290, which is an oral agent.

         13. Has been administered a live vaccine within 4 weeks (28 days) of initiation of study
             therapy. Patients are eligible if 28 days have elapsed since receipt of vaccine and
             initiation of study treatment. (NOTE: seasonal vaccines for influenza are generally
             inactivated vaccines and are allowed. Intranasal vaccines are live vaccines; and are
             not allowed).

         14. 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part A: Number of participants with treatment-related adverse events as assessed by CTCAE v4.03
Time Frame:from the day of first administration of study drugs up to 30 days after the last administration of BGB-290 and up to 120 days after the last administration of BGB-A317
Safety Issue:
Description:Safety and tolerability as assessed by the incidence and nature of AEs.

Secondary Outcome Measures

Measure:Part A: Pharmacokinetic parameters, including but not limited to Ctrough of BGB-A317
Time Frame:pre-dose and at 4 hours in Cycles 2 (each cycle is 21 days), 3 and 4
Safety Issue:
Description:
Measure:Part A: Pharmacokinetic parameters, including but not limited to Cmax of BGB-290
Time Frame:pre-dose and at 4 hours in Cycles 2 (each cycle is 21 days), 3 and 4
Safety Issue:
Description:
Measure:Part A: Pharmacokinetic parameters, including but not limited to Tmax of BGB-290
Time Frame:pre-dose and at 4 hours in Cycles 2 (each cycle is 21 days), 3 and 4
Safety Issue:
Description:
Measure:Part A: Pharmacokinetic parameters, including but not limited to Ctrough of BGB-290
Time Frame:pre-dose and at 4 hours in Cycles 2 (each cycle is 21 days), 3 and 4
Safety Issue:
Description:
Measure:Part A: Disease response as determined by Overall Response Rate per RECIST Version 1.1
Time Frame:From randomisation until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.
Safety Issue:
Description:Anti-tumor activity as determined by the ORR. Radiological assessment of tumor response should be performed approximately every 9 ± 1 weeks in the first 12 months and approximately every 12 ± 1 weeks from screening until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.
Measure:Part A: Disease response as determined by Progression Free Survival per RECIST Version 1.1
Time Frame:From randomisation until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.
Safety Issue:
Description:Anti-tumor activity as determined by the PFS. Radiological assessment of tumor response should be performed approximately every 9 ± 1 weeks in the first 12 months and approximately every 12 ± 1 weeks from screening until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.
Measure:Part A: Disease response as determined by Duration of Response per RECIST Version 1.1
Time Frame:From randomisation until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.
Safety Issue:
Description:Anti-tumor activity as determined by the DOR. Radiological assessment of tumor response should be performed approximately every 9 ± 1 weeks in the first 12 months and approximately every 12 ± 1 weeks from screening until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.
Measure:Part A: Disease response as determined by Disease Control Rate per RECIST Version 1.1
Time Frame:From randomisation until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.
Safety Issue:
Description:Anti-tumor activity as determined by the DCR. Radiological assessment of tumor response should be performed approximately every 9 ± 1 weeks in the first 12 months and approximately every 12 ± 1 weeks from screening until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.
Measure:Part A: Disease response as determined by Clinical Benefit Rate per RECIST Version 1.1
Time Frame:From randomisation until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.
Safety Issue:
Description:Anti-tumor activity as determined by the CBR. Radiological assessment of tumor response should be performed approximately every 9 ± 1 weeks in the first 12 months and approximately every 12 ± 1 weeks from screening until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.
Measure:Part A: Disease response as determined by overall survival
Time Frame:From randomisation until the patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.
Safety Issue:
Description:Anti-tumor activity as determined by the OS.
Measure:Part A: Immunogenicity of BGB-A317
Time Frame:Blood for anti-BGB-A317 antibodies should be collected within 24 hours before the start of the first dose of BGB-A317 in Cycle 1, and Day 8 of Cycle 1, Day 1 of Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 9 and Cycle 17
Safety Issue:
Description:
Measure:Part B: Safety and tolerability as assessed by the incidence and nature of AEs
Time Frame:from the day of first administration of study drugs up to 30 days after the last administration of BGB-290 and up to 120 days after the last administration of BGB-A317
Safety Issue:
Description:
Measure:Part B: Pharmacokinetic parameters, including but not limited to Ctrough of BGB-A317 and BGB-290
Time Frame:Pre-dose in Cycle 1 (day 1 and day 7 - 10), and Cycles 2, 3, 4 5, 9 & 17. At 4 hours in Cycles 1 & 5 (each cycle is 21 days)
Safety Issue:
Description:
Measure:Part B: Immunogenicity of BGB-A317
Time Frame:Cycle 1 (Day 1 & Day 7 - 10), and Day 1 of Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 9 and Cycle 17
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:BeiGene

Trial Keywords

  • Dose Escalation
  • Dose Expansion
  • BGB-A317
  • BGB-290

Last Updated

November 21, 2017