Clinical Trials /

First-in-Human Study of the SHP2 Inhibitor BBP-398 in Patients With Advanced Solid Tumors

NCT04528836

Description:

A first-in-human study is to evaluate the safety, tolerability and maximum tolerated dose (MTD) and establish the recommended phase 2 dose (RP2D) of BBP-398, a SHP2 inhibitor, in patients with advanced solid tumors.

Related Conditions:
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: First-in-Human Study of the SHP2 Inhibitor BBP-398 in Patients With Advanced Solid Tumors
  • Official Title: A Phase 1/1B First-in-Human Study of the SHP2 Inhibitor BBP-398 (Formerly Known as IACS-15509) in Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: NAV-1001
  • NCT ID: NCT04528836

Conditions

  • Tumor, Solid

Interventions

DrugSynonymsArms
BBP-398 (Formerly Known as IACS-15509)Dose Escalation Level 1

Purpose

A first-in-human study is to evaluate the safety, tolerability and maximum tolerated dose (MTD) and establish the recommended phase 2 dose (RP2D) of BBP-398, a SHP2 inhibitor, in patients with advanced solid tumors.

Detailed Description

      The first-in-human (FIH) study of BBP-398 will be an open-label, sequential-cohort,
      non-randomized, Phase 1/1B study utilizing BOIN dose escalation followed by an expansion
      phase in patients with MAPK pathway- or RTK-driven advanced solid tumors. The primary
      objective is to determine safety and tolerability of BBP-398, the MTD and RP2D. The secondary
      objectives are to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profile,
      preliminary anti-tumor activity, objective response rate (ORR, complete response + partial
      response rate) and the duration of response (DoR) of BBP-398. The exploratory objective is to
      assess predictive biomarkers of response.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation Level 1Experimental80 mg/ oral capsules. Each treatment cycle will be 28 days in duration with BBP-398 administered, once daily (QD).
  • BBP-398 (Formerly Known as IACS-15509)
Dose Escalation Level 2Experimental150 mg/ oral capsules. Each treatment cycle will be 28 days in duration with BBP-398 administered, once daily (QD).
  • BBP-398 (Formerly Known as IACS-15509)
Dose Escalation Level 3Experimental250 mg/ oral capsules. Each treatment cycle will be 28 days in duration with BBP-398 administered, once daily (QD).
  • BBP-398 (Formerly Known as IACS-15509)
Dose Escalation Level 4Experimental400 mg/ oral capsules. Each treatment cycle will be 28 days in duration with BBP-398 administered, once daily (QD).
  • BBP-398 (Formerly Known as IACS-15509)
Dose Escalation Level 5Experimental550 mg/ oral capsules. Each treatment cycle will be 28 days in duration with BBP-398 administered, once daily (QD).
  • BBP-398 (Formerly Known as IACS-15509)
Dose Escalation Level 6Experimental700 mg/ oral capsules. Each treatment cycle will be 28 days in duration with BBP-398 administered, once daily (QD).
  • BBP-398 (Formerly Known as IACS-15509)
Expansion Cohort A: Advanced KRAS G12C NSCLCExperimentalMTD/RP2D defined dose. Oral capsules Each treatment cycle will be 28 days in duration with BBP-398 administered, once daily (QD)
  • BBP-398 (Formerly Known as IACS-15509)
Expansion Cohort B: Advanced KRAS G12C non-NSCLCExperimentalMTD/RP2D defined dose. Oral capsules Each treatment cycle will be 28 days in duration with BBP-398 administered, once daily (QD)
  • BBP-398 (Formerly Known as IACS-15509)
Expansion Cohort C: Advanced solid tumor with other MAPK-ExperimentalMTD/RP2D defined dose. Oral capsules Each treatment cycle will be 28 days in duration with BBP-398 administered, once daily (QD)
  • BBP-398 (Formerly Known as IACS-15509)
Expansion Cohort D: Advanced EGFR-mutant NSCLCExperimentalMTD/RP2D defined dose. Oral capsules Each treatment cycle will be 28 days in duration with BBP-398 administered, once daily (QD)
  • BBP-398 (Formerly Known as IACS-15509)

Eligibility Criteria

        Inclusion

          1. Male and non-pregnant females >18 years old.

          2. Patients must have a diagnosis of advanced (primary or recurrent) or metastatic solid
             tumor with MAPK-pathway alterations (excluding BRAF V600X) as assessed by clinically
             validated and/or FDA-approved molecular diagnostic and no available standard of care
             or curative therapies (MAPK-pathway alterations include, for example KRASG12C mutant,
             EGFR-mutant; see Appendix 1).

          3. Dose expansion only: Patients with the following genomically defined tumor types will
             be recruited:

               -  Advanced or metastatic KRASG12C mutant non-small cell lung cancer (NSCLC) with no
                  available standard of care or curative therapies

               -  Advanced or metastatic KRASG12C mutant solid tumor other than NSCLC with no
                  available standard of care or curative therapies

               -  Advanced or metastatic solid tumor with other MAPK-pathway alterations (excluding
                  BRAF V600X) with no available standard of care or curative therapies

               -  Advanced or metastatic EGFR-mutant NSCLC, that progressed on standard of care
                  EGFR TKI therapies, with no available standard of care or curative therapies

          4. Biopsies are optional. Optionally, patients may have available a fresh or recent tumor
             tissue sample from a diagnostic biopsy/surgery or a metastatic tumor biopsy; the
             sample must have been obtained within 12 months prior to study enrollment and must be
             available for study use. For subjects in dose levels starting at dose level 4
             (including dose expansion): Patients must have available a fresh or recent tumor
             tissue sample from a diagnostic biopsy/surgery or a metastatic tumor biopsy; the
             sample must have been obtained within 12 months prior to study enrollment and must be
             available for study use. Note: patients may be enrolled based on liquid biopsy next
             generation sequencing results with tumor tissue for confirmation.

          5. Patients must have measurable disease by RECIST v1.1.

          6. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status
             (PS) 0-2 (see Appendix 2).

          7. Patients must have adequate organ function as defined below:

             Hematological

               -  Absolute neutrophil count (ANC) ≥1,500/mcL

               -  Platelets ≥100,000/mcL

               -  Hemoglobin ≥10 g/dL without transfusion for >2 weeks or
                  erythropoiesis-stimulating agents (e.g., Epo, Procrit) for >6 weeks Renal

               -  Calculated creatinine clearance ≥60 mL/min/1.73 m2 (calculated by the
                  Cockcroft-Gault formula) Hepatic

               -  Serum total bilirubin ≤1.5X institutional ULN or direct bilirubin ≤2x
                  institutional ULN if total bilirubin levels >1.5x institutional ULN for subjects
                  without Gilbert syndrome; serum total bilirubin ≤2x institutional ULN for
                  subjects with documented Gilbert syndrome

               -  AST(SGOT)/ALT(SGPT) <2.5X ULN or <5X ULN in the presence of liver metastases
                  Coagulation

               -  International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5xULN unless the
                  patient is receiving anticoagulant therapy as long as PT or PTT is within the
                  therapeutic range of intended use of anticoagulants.

               -  Activated Partial Thromboplastin Time (aPTT) ≤1.5xULN unless the patient is
                  receiving anticoagulant therapy as long as PT or PTT is within the therapeutic
                  range of intended use of anticoagulants.

          8. Patients must be ≥3 weeks beyond treatment with any chemotherapy or other
             investigational therapy to include hormonal (including corticosteroids), biological,
             or targeted agents; or at least 5 half-lives from hormonal (including
             corticosteroids), biological, or targeted agents, whichever is longer at the time of
             treatment initiation.

          9. Women of childbearing potential (WOCBP) MUST have a negative serum or urine HCG test
             unless prior tubal ligation (≥1 year prior to screening), total hysterectomy or
             menopause (defined as 12 consecutive months of amenorrhea and confirmed by follow up
             hormone level assessment).

         10. Female patients should not become pregnant or breastfeed while on this study. Patients
             of childbearing potential must use 2 methods of contraception for the duration of the
             study and for at least 90 days after the last dose of study drugs for female patients
             or 105 days after the last dose of study drugs for male patients, whichever is later
             for the individual patient. Adequate methods of contraception include:

               -  Total abstinence when this is in line with the preferred and usual lifestyle of
                  the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
                  post-ovulation methods) and withdrawal are not acceptable methods of
                  contraception.

               -  Female sterilization (have had surgical bilateral oophorectomy with or without
                  hysterectomy) or tubal ligation at least six weeks before taking study treatment.
                  In case of oophorectomy alone, only when the reproductive status of the woman has
                  been confirmed by follow up hormone level assessment.

               -  Male sterilization (at least 6 months prior to screening with documented
                  infertility). For female patients on the study, the vasectomized male partner
                  should be the sole partner for that subject.

               -  Combination of any of the two following (a+b or a+c or b+c)

                    1. Use of oral, injected or implanted hormonal methods of contraception or
                       other forms of hormonal contraception that have comparable efficacy (failure
                       rate <1%), for example hormone vaginal ring or transdermal hormone
                       contraception

                    2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

                    3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
                       cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal
                       suppository In case of use of oral contraception, women should have been
                       stable on the same pill for at least 90 days before taking study treatment.

         11. Patients must have the ability to understand and the willingness to sign a written
             informed consent document prior to the initiation of the study and any study
             procedures.

         12. Patients must be willing and able to comply with the scheduled visits, treatment plan,
             laboratory tests and other specified study procedures.

        Exclusion Criteria

          1. Patients with known active Hepatitis B, Hepatitis C infection, or HIV infection with
             measurable viral load.

          2. Patients with active infection requiring intravenous (IV) antibiotics or other
             uncontrolled intercurrent illness requiring hospitalization. Minor infections, e.g.,
             periodontal infection or urinary tract infection (UTI), which may be treated with
             short term oral antibiotics are allowed.

          3. Patients with a history of CVA, myocardial infarction or unstable angina within the
             previous 6 months before starting therapy.

          4. Patients with clinically significant cardiac disease, including New York Heart
             Association Class II or higher.

          5. Patients with a history of LVEF <50% within the previous 12 months.

          6. Patients with a history of retinal vein occlusion (RVO) or current risk factors for
             RVO.

          7. Patients with tumors harboring known activating mutations in BRAF V600X or PTPN11
             (SHP2).

          8. Patients with a known additional malignancy that is progressing or requires active
             treatment. Exceptions include basal cell carcinoma of the skin, squamous cell
             carcinoma of the skin that has undergone potentially curative therapy or in situ
             cervical cancer.

          9. Patients with known central nervous system (CNS) tumors.

         10. Patients with known active CNS metastases and/or carcinomatous meningitis. Patients
             with previously treated brain metastases may participate provided they are stable
             (without evidence of progression by imaging for at least four weeks prior to the first
             dose of trial treatment and any neurologic symptoms have returned to baseline), have
             no evidence of new or enlarging brain metastases, and are not using steroids for at
             least 7 days prior to trial treatment. This exception does not include carcinomatous
             meningitis which is excluded regardless of clinical stability.

         11. Patients who have undergone major surgery within 4 weeks prior to study enrollment.

             Note: This does not include patients who have had procedures such as PICC line
             placement, thoracocentesis, paracentesis, biopsies, or abscess drainage.

         12. Patients who have previously received a SHP2 inhibitor (e.g., TNO-155, RMC-4630,
             RLY-1971).

         13. Dose expansion only: Patients who have previously received a KRASG12C inhibitor.

         14. Patients who have received strong or moderate inducers or inhibitors of CYP3A4 or P-gp
             inducers or inhibitors (including herbal supplements) within 7 days of Cycle 1 Day 1.

         15. Patients who have received drugs that are known substrates of P-gp, BCRP, OATP1B1,
             OATP1B3, MATE1 and MATE2-K transporters within 7 days of Cycle 1 Day 1.

         16. Any condition or therapy, which, in the opinion of the Investigator, might pose a risk
             to the patient, impair participation or cooperation, or might confound the ability to
             interpret study data.

         17. Patients with inability to swallow oral medications (capsules, tablets) without
             chewing, breaking, crushing, opening or otherwise altering the product dosage form.

         18. Patients should not have gastrointestinal illness that, in the opinion of the
             investigator, would preclude the absorption of BBP-398, which is an oral agent.

         19. Patients on dialysis.

         20. Female patients who are pregnant, planning to become pregnant, or who are
             breastfeeding.

         21. Any patient, who in the opinion of the investigator, is likely to be unable to comply
             with the study procedures.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determination of Maximum Tolerated Dose (MTD) of BBP-398.
Time Frame:Completion of 1 Cycle ( 28 days)
Safety Issue:
Description:The MTD will be determined as the dose for which the isotonic estimate of the DLT rate is closest to 27%.

Secondary Outcome Measures

Measure:Determination of anti-tumor activity of BBP-398
Time Frame:Completion of 1 Cycle ( 28 days)
Safety Issue:
Description:Anti-tumor activity will be defined by objective response rate (ORR2, complete response + partial response rate) and duration of response (DOR3)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Navire Pharma Inc.

Trial Keywords

  • Cancer
  • MAPK-pathway alterations

Last Updated

December 3, 2020