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 :
- 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).
- 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.
- Number of Participants Reporting One or More Treatment Emergent Serious Adverse Event (SAEs) [ Time Frame: Up to 30 months ]
- Number of Participants With one or More TEAEs Leading to Dose Modifications and Treatment Discontinuations [ Time Frame: Up to 30 months ]
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
- Life expectancy >12 weeks, as assessed by the investigator.
- 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.
- 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.
- Adequate bone marrow, renal, hepatic and cardiac functions.
- 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.
- 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.
- 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.
- Must have at least 1 RECIST v.1.1-evaluable (measurable or nonmeasurable) lesion.
- 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.
- Corrected QT interval by Fredericia (QTcF) greater than (>) 450 milliseconds (men) or >475 milliseconds (women) on a 12-lead ECG during the screening period.
- Grade greater than or equal to (>=) 2 hypotension (that is, hypotension for which nonurgent intervention is required) at screening or during C1D1 predose assessment.
- Oxygen saturation less than (<) 92 percent (%) on room air at screening or during C1D1 predose assessment.
- Treated with other STING agonists/antagonist and TLR agonists within the past 6 months.
- Active vaping within 90 days of C1D1 of study drug(s).
- Active smoking.
- 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.
- History of brain metastasis unless:
- Clinically stable (that is, >=6 weeks) following prior surgery, whole-brain radiation, or stereotactic radiosurgery, AND
- Off corticosteroids.
- Ongoing Grade >= 2 infection or participants with Grade >=2 fever of malignant origin.
- Chronic, active hepatitis (example: participants with known hepatitis B surface antigen seropositive and/or detectable hepatitis C virus [HCV]-RNA).
- For participants in the SA arm only: refusal of standard therapeutic options.
- For participants in the combination arm only: contraindication and/or intolerance to the administration of pembrolizumab.
- 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).
- 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.
- 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).
- Use of medications that are known clinical OATP1B1 and/or OATP1B3 inhibitors, concurrently or within 14 days of C1D1 of study drug(s).
- Receipt of live attenuated vaccine within 28 days of C1D1 of study drug(s).
- Recipients of allogeneic or autologous stem cell transplantation or organ transplantation.