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Phase I

An Open-label, Dose Escalation, Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-676 as a Single Agent and in Combination With Pembrolizumab in Adult Patients With Advanced or Metastatic Solid Tumors

  • Study HIC#:2000027564
  • Last Updated:12/22/2022

The purpose of this study is to determine the safety and tolerability of TAK-676 administered as an SA or in combination with pembrolizumab in participants with advanced or metastatic solid tumors.

  • Start Date12/01/2020
  • End Date03/11/2023

Trial Purpose and Description

Primary Outcome Measures  :

  1. Number of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs) and Based on TEAEs Severity [ Time Frame: Up to 30 months ]A severity grade is defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. Grade 1 scales as Mild (asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated); Grade 2 scales as Moderate (minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living [ADL]); Grade 3 scales as Severe (severe or medically significant but not immediately life threatening hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL); Grade 4 scales as Life-threatening consequences, urgent intervention indicated, and Grade 5 scales as Death related to Adverse Event (AE).
  2. Number of Participants with Dose-Limiting Toxicities (DLTs) [ Time Frame: Up to 30 months ]A DLT will be defined as any of the TEAEs, but not limited to, those that occur during Cycle 1 and are considered by the investigator to be at least possibly related to TAK-676 as an SA or in combination with pembrolizumab. TEAEs meeting DLT definitions occurring in Cycle 2 or later will be considered in the determination of the recommended phase 2 dose (RP2D) of TAK-676, both in the TAK-676 SA and the combination with pembrolizumab arms. Toxicity will be evaluated according to NCI CTCAE version 5.0.
  3. Number of Participants Reporting One or More Treatment Emergent Serious Adverse Event (SAEs) [ Time Frame: Up to 30 months ]
  4. Number of Participants With one or More TEAEs Leading to Dose Modifications and Treatment Discontinuations [ Time Frame: Up to 30 months ]

Eligibility Criteria

Inclusion Criteria:

  1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
  2. Life expectancy >12 weeks, as assessed by the investigator.
  3. TAK-676 SA:

    o With histologically confirmed (cytological diagnosis is acceptable) advanced or metastatic solid tumors that have no standard therapeutic options or are intolerant to these therapies.

  4. TAK-676 in combination with pembrolizumab:

    o With histologically confirmed (cytological diagnosis is acceptable) advanced or metastatic solid tumors, including:

    • Tumors that have relapsed or are refractory to anti-programmed cell death protein 1 (anti-PD-1)/anti-programmed cell death ligand 1 (anti-PD-L1) therapy.
    • Tumors that are naive to anti-PD-1/ anti-PD-L1 therapy.
  5. Adequate bone marrow, renal, hepatic and cardiac functions.
  6. Left ventricular ejection fraction (LVEF) >50%, as measured by echocardiogram or multiple-gated acquisition (MUGA) scan within 4 weeks before receiving the first dose of study drug.
  7. Clinically significant toxic effects of previous therapy have recovered to Grade 1 (per NCI CTCAE Version 5.0) or baseline, except for alopecia, Grade 2 peripheral neuropathy, and/or autoimmune endocrinopathies with stable endocrine replacement therapy.
  8. Once peripheral evidence of TAK-676 pharmacodynamic stimulation of the innate and/or adaptive immune system is observed in the blood and/or clinical response (CR/PR) is observed in at least 1 participant, subsequent participants must:
    • Have at least 1 lesion amenable for biopsy.
    • Agree to have 2 tumor biopsies: 1 during the screening period and 1 while on TAK-676 treatment.
  9. Must have at least 1 RECIST v.1.1-evaluable (measurable or nonmeasurable) lesion.
  10. PK/pharmacodynamic blood must be drawn on a peripherally-inserted catheter. TAK-676 is preferentially administered through a central line, but peripheral infusion is acceptable. If a peripheral line is used for TAK-676 and/or pembrolizumab infusion, it must be separate than the one used for PK/ pharmacodynamic collection.

Exclusion Criteria:

  1. Corrected QT interval by Fredericia (QTcF) greater than (>) 450 milliseconds (men) or >475 milliseconds (women) on a 12-lead ECG during the screening period.
  2. Grade greater than or equal to (>=) 2 hypotension (that is, hypotension for which nonurgent intervention is required) at screening or during C1D1 predose assessment.
  3. Oxygen saturation less than (<) 92 percent (%) on room air at screening or during C1D1 predose assessment.
  4. Treated with other STING agonists/antagonist and TLR agonists within the past 6 months.
  5. Active vaping within 90 days of C1D1 of study drug(s).
  6. Active smoking.
  7. Current history of pneumonitis, interstitial lung disease, severe chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, other restrictive lung diseases, acute pulmonary embolism, or Grade >=2 pleural effusion or ascites not controlled by tap or requiring indwelling catheters.
  8. History of brain metastasis unless:
    • Clinically stable (that is, >=6 weeks) following prior surgery, whole-brain radiation, or stereotactic radiosurgery, AND
    • Off corticosteroids.
  9. Ongoing Grade >= 2 infection or participants with Grade >=2 fever of malignant origin.
  10. Chronic, active hepatitis (example: participants with known hepatitis B surface antigen seropositive and/or detectable hepatitis C virus [HCV]-RNA).
  11. For participants in the SA arm only: refusal of standard therapeutic options.
  12. For participants in the combination arm only: contraindication and/or intolerance to the administration of pembrolizumab.
  13. Concurrent chemotherapy, immunotherapy (except for pembrolizumab in the combination arm), biologic, or hormonal therapy (except for adjuvant endocrine therapy for a history of breast cancer). Concurrent use of hormones for noncancer-related conditions is acceptable (except for corticosteroid hormones).
  14. Radiation therapy within 14 days (42 days for radiation to the lungs) and/or systemic treatment with radionuclides within 42 days before C1D1 of study drug(s). Participants with clinically relevant ongoing pulmonary complications from prior radiation therapy are not eligible.
  15. Use of systemic corticosteroids or other immunosuppressive therapy, concurrently or within days of C1D1 of study drug(s), with the following exceptions:
    • Topical, intranasal, inhaled, ocular, and/or intra-articular corticosteroids.
    • Physiological doses of replacement steroid therapy (example: for adrenal insufficiency).
  16. Use of medications that are known clinical OATP1B1 and/or OATP1B3 inhibitors, concurrently or within 14 days of C1D1 of study drug(s).
  17. Receipt of live attenuated vaccine within 28 days of C1D1 of study drug(s).
  18. Recipients of allogeneic or autologous stem cell transplantation or organ transplantation.

Sub-Investigators

For more information about this study, contact: