MC# 20-08 - An Open-label, Dose Escalation, Phase I 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 TAK-676 as Single Agent and in Combination With Pembrolizumab in Advanced or Metastatic Solid Tumors

  • Agent(s): TAK-676
  • Disease Type(s): Colorectal, Solid Tumor, Squamous Cell Carcinoma of Head and Neck
  • Phase(s): I
  • Drug Classification(s): Immunotherapy, Targeted Therapy
  • Molecular Target(s): STING
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Mechanism of Action

TAK-676 is a synthetic cyclic dinucleotide (CDN) exhibiting highly selective binding and activation of STING pathway.

Purpose

In this study, the sponsor and investigators want to learn:

  • How much of TAK-676 can be given with an acceptable level of side effects
  • About the safety and tolerability of TAK-676 alone and in combination with Pembrolizumab
  • How proteins that indicate the status of your immune system are affected with use of TAK-676 alone and in combination with Pembrolizumab
  • If TAK-676 alone and in combination with Pembrolizumab prevents or delays tumor growth or shrinks existing tumors
  • How quickly TAK-676 is removed from your blood stream
Inclusion Criteria
  1. Adult male or female patients aged 18 years or older.
  2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
  3. Not applicable. In Protocol Amendment 4, the requirement for patients to have a life expectancy of >12 weeks was removed.
  4. TAK-676 SA (dose escalation Part 1A):
    • Patients with histologically confirmed (cytological diagnosis is acceptable) advanced or metastatic solid tumors that have no standard therapeutic options or are intolerant to these therapies. Intolerant patients are those who have developed clinical or laboratory abnormalities that prevent continued drug administration as evaluated by the principal investigator at the time of screening.
  5. TAK-676 in combination with pembrolizumab (dose escalation Part 1B):
    • Patients with histologically confirmed (cytological diagnosis is acceptable) advanced or metastatic solid tumors that have no standard therapeutic options or are intolerant to them, including:
      • Tumors that have relapsed or are refractory to anti-PD-1/anti-PD-L1 therapy.
        • Refractory tumors are defined as those that progressed by either clinical or radiographic assessment at the first evaluation point after initiation of anti-PD-1/anti-PD-L1 treatment. Relapsed tumors are defined as those that progressed by either clinical or radiographic assessment at any evaluation point thereafter.
      • Tumors that are naïve to anti-PD-1/anti-PD-L1 therapy, including but not limited to the following tumor types of interest:
        • Tumors with no health authority-approved indication for pembrolizumab use.
        • Tumors with limited response to anti-PD-1/anti-PD-L1 therapy and having a health authority-approved indication for pembrolizumab use.
  6. For expansion phase only
    1. SCCHN (Part 2):
      • Patients with histologically confirmed (cytological diagnosis is acceptable) metastatic or unresectable, recurrent SCCHN that is considered incurable by local therapies. Subjects should not have had prior systemic therapy administered in the recurrent or metastatic setting. Systemic therapy which was completed more than 6 months before signing consent if given as part of multimodal treatment of locally advanced disease is allowed.
      • Anatomic subsites to be included are oral cavity, oropharynx, hypopharynx, larynx, nasal cavity, and paranasal sinuses (maxillary, ethmoid, sphenoid, and frontal). The exception to this is nasopharyngeal cancer and salivary gland tumors, which will not be included.
      • Patients with oropharyngeal cancer or tumors arising in the paranasal sinuses (maxillary, ethmoid, sphenoid, and frontal) must agree to provide archival tissue for HPV testing or if known, HPV testing results using CINtec® p16 Histology assay and a 70% cutoff point must be provided. If HPV status was previously tested using this method, no additional testing is required.
      • For Part 2A, tumors must have a CPS ≥ 1. For Part 2B, any CPS is eligible.
      • For Part 2B, patients must be eligible to receive treatment with either cisplatin or carboplatin in combination with 5-FU per the treating physician.
    2. CRC (Part 3):
      • Third-line or later MSI-H/dMMR CRC (Part 3A): Patients with histologically confirmed (cytological diagnosis is acceptable) recurrent locally advanced or metastatic MSI-H/dMMR CRC whose disease has progressed on or following therapy with 1) an anti-PD-1 or PD-L1 antibody (ie, pembrolizumab) and 2) at least one line of combination chemotherapy including a fluoropyrimidine and irinotecan OR oxaliplatin with or without an anti-EGFR or anti-VEGFR monoclonal antibody (ie, cetuximab or bevacizumab). MSI-H/dMMR CRC patients must have received at least 6 weeks of prior treatment with an anti-PD-1 or anti-PD-L1 antibody.
      • Third-line MSS/pMMR CRC (Part 3B): Patients with histologically confirmed (cytological diagnosis is acceptable) recurrent locally advanced or metastatic MSS/pMMR CRC whose disease has progressed on or following therapy with 2 different lines of combination chemotherapy, including therapy with a fluoropyrimidine and irinotecan AND therapy with a fluoropyrimidine and oxaliplatin. Both lines of therapy may be given with or without an anti-EGFR or anti-VEGFR monoclonal antibody (ie, cetuximab or bevacizumab). Subjects with MSS/pMMR CRC must have progressed on or after combination chemotherapy regimens containing BOTH irinotecan AND oxaliplatin.
      • Patients with MSI-H/dMMR or MSS/pMMR CRC must have MSI/MMR status confirmed by a clinically-approved immunohistochemistry (IHC) and/or polymerase chain reaction (PCR) assay.
      • Patients with MSI-H/dMMR or MSS/pMMR CRC must have been treated with 2 prior lines of therapy in the recurrent locally advanced or metastatic setting.
  7. Adequate bone marrow, renal, and hepatic functions
  8. 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.
  9. 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.
  10. Patients must have at least 1 RECIST v.1.1–evaluable measurable lesion. For the dose escalation phase (Part 1) only, nonmeasurable only disease is acceptable.
  11. Female patients must be:
    1. Postmenopausal (natural amenorrhea and not due to other medical reasons) for at least 1 year before the screening visit, OR
    2. Surgically sterile, OR
    3. If they are of childbearing potential, agree to practice 2 effective methods of contraception (see Section 8.9) at the same time, from the time of signing the informed consent through 120 days after the last dose of study drug(s), OR
    4. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.
  12. Male patients, even if surgically sterilized (ie, status postvasectomy), must:
    1. Agree to practice effective barrier contraception (see Section 8.9) during the entire study treatment period and through 120 days after the last dose of study drug, OR
    2. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.
Exclusion Criteria
  • 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
  • Patients treated with other STING agonists/antagonist and toll-like receptor agonists within the past 6 months
  • Active smoking
  • Active vaping within 90 days of C1D1 of study drug(s)
  • Current history of pneumonitis, interstitial lung disease, severe chronic obstructive pulmonary disease, 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 patients with Grade ≥2 fever of malignant origin
  • Known history of uncontrolled autoimmune disorders, HIV infection, or other relevant congenital or acquired immunodeficiencies
  • Chronic, active hepatitis (eg, patients with known hepatitis B surface antigen seropositive and/or detectable hepatitis C virus [HCV]-RNA)
  • For patients in the dose escalation SA Part 1A only: refusal of standard therapeutic options
  • For patients receiving pembrolizumab only: contraindication and/or intolerance to the administration of pembrolizumab. For patients receiving chemotherapy in Part 2B: contraindication and/or intolerance to the administration of both platinum agents (cisplatin and carboplatin) and/or 5-FU.
  • Concurrent chemotherapy (except fro Part 2B), immunotherapy (except for pembrolizumab in Part 1B, Part 2, and Part 3), 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).  Patients with clinically relevant ongoing pulmonary complications from prior radiation therapy are not eligible.
  • Use of systemic corticosteroids or other immunosuppressive therapy, concurrently or within 7 days of C1D1 of study drug(s), with the following exceptions:
    • Topical, intranasal, inhaled, ocular, intra-articular, and/or other nonsystemic corticosteroids
    • Physiological doses of replacement steroid therapy (eg, for adrenal insufficiency)
    • For patients enrolled in Part 2B, chemotherapy premedication with steroids can be administered according to local standards of care practice
  • 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 (eg, tuberculosis Bacillus Calmette-Guerin vaccine, oral polio vaccine, measles, rotavirus, yellow fever) within 28 days of C1D1 of study drug(s)
  • Recipients of allogeneic or autologous stem cell transplantation or organ transplantation

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT04420884

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Re: MC# 20-08