This Phase 1/2, open-label study will characterize safety and dose-limiting toxicities (DLTs) of TAK-186. Dose escalation will occur in participants with advanced solid tumors. A Cohort Expansion Phase will be enrolled to further characterize safety and initial anti-tumor activity in participants with solid tumors expressing epidermal growth factor receptor (EGFR), including HNSCC, CRC or NSCLC.
Key Inclusion Criteria:
- Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
- Ability to provide informed consent and documentation of informed consent before
initiation of any study-related tests or procedures that are not part of standard of
care for the participant's disease. Participants must also be willing and able to
comply with study procedures, including the acquisition of specified research
specimens.
- Life expectancy ≥ 12 weeks
- Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
criteria and documented by Computed tomography (CT) and/or magnetic resonance imaging
(MRI). The definitions for measurable lesions are the same whether conventional and
modified RECIST criteria are applied. Cutaneous or subcutaneous lesions must be
measurable by calipers. Lesions to be used as measurable disease for the purpose of
response assessment must either a) not reside in a field that has been subjected to
prior radiotherapy, or b) have demonstrated clear evidence of radiographic progression
since the completion of prior radiotherapy and before study enrollment or c) have been
radiated at least 6 months before study enrollment.
- Tumor Histology Types:
- Participants with pathologically proven, unresectable, locally advanced or metastatic
solid tumors that based on literature reports are considered to express EGFR. During
cohort expansion, participants with locally advanced or metastatic solid tumors
expressing EGFR including advanced or metastatic NSCLC, CRC, and HNSCC are eligible
for enrollment.
* Tumors During Cohort Expansion:
- Participants with pathologically proven, unresectable, locally advanced or metastatic
solid tumors that based on literature reports are considered to express EGFR are
eligible for enrollment:
- NSCLC: locally advanced or metastatic NSCLC that has progressed during or
following treatment with platinum-based chemotherapy, a checkpoint inhibitor
(unless known to be PD-L1 negative), or targeted therapy (for participants with a
known actionable mutation).
- CRC: locally advanced or metastatic CRC that has progressed after systemic
therapies, including irinotecan, oxaliplatin, an anti-EGFR inhibitor (if K-RAS or
N-RAS is WT), a checkpoint inhibitor (if MSI-H), and a VEGF inhibitor (if locally
approved and accessible as a standard-of-care).
- HNSCC: HNSCC that has progressed during or following treatment with a checkpoint
inhibitor (unless ineligible, e.g, PD-L1 negative) and platinum-based
chemotherapy (unless ineligible for or intolerant to platinum-based chemotherapy)
with or without cetuximab for metastatic or recurrent disease.
1. Participants with salivary gland tumors will not be considered as having
HNSCC.
2. Participants who refuse surgery for potentially curable disease where the
surgery or radiotherapy could result in severe morbidity are eligible. The
reason for the refusal will be captured in the electronic case report form
(eCRFs).
- Archival Tissue:
- Participants must allow acquisition of existing formalin-fixed paraffin-embedded
(FFPE) archival tumor sample, either a block or unstained slides. Participants who
provide fresh pretreatment biopsy samples will not be required to submit archival
tumor samples.
- Tumor Biopsy:
• Participants must be willing to consent to mandatory pretreatment (during
screening) and on-treatment fresh tumor biopsies for cohort expansion phase and
backfill in dose escalation. Once the target number of biopsies have been
collected, additional paired pretreatment and on-treatment biopsies will not be
required; sample collection will be optional after this time point. For fresh
tumor biopsies, the lesion must be accessible (those occurring outside the brain
or those that are accessible by an interventional or endoscopic procedure) for a
low-risk biopsy procedure that does not place the participant at an unjustifiable
risk in the opinion of the investigator. Participants who have an archived biopsy
specimen available that was obtained up to 90 days prior to treatment initiation
and have received no other treatment from the time of biopsy until the start of
treatment with TAK-186, may submit that archived specimen in lieu of a
pretreatment biopsy upon agreement from the sponsor.
- Laboratory Features:
- Acceptable laboratory parameters as follows:
1. Albumin ≥ 3.0 g/dL
2. Platelet count ≥ 75 × 103/μL
3. Hemoglobin ≥ 9.0 g/dL
4. Absolute neutrophil count ≥ 1.0 × 103/μL
5. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3.0 × upper
limit of normal (ULN); for participants with hepatic metastases, ALT/AST ≤ 5 ×
ULN
6. Total bilirubin ≤ 1.5 × ULN, except participants with Gilbert's syndrome, who may
enroll if the conjugated bilirubin is within normal limits.
7. Creatinine clearance of ≥ 30 mL/minute using Cockcroft-Gault equation.
- Reproductive Features:
- WOCBP must have a negative serum pregnancy test performed within 72 hours before the
initiation of study drug administration. WOCBP must use 1 form of highly effective
method and 1 additional effective (barrier) method of contraception at the same time
throughout the study, starting at screening through 90 days after the last dose of
TAK-186. Contraception methods may be considered highly effective if they can achieve
a failure rate of less than 1% per year when used consistently and correctly.
- Male participants with partners of childbearing potential must use barrier
contraception during the entire study treatment period through 120 days after the last
dose of study drug and must not donate sperm during this period. In addition, male
participants should also have their partners use contraception (as documented for
female participants) for the same period of time.
* Previous Checkpoint Inhibitor Therapy:
- Participants who have previously received an immune checkpoint before enrollment must
have checkpoint inhibitor immune-related toxicity resolved to either Grade ≤ 1 or
baseline
- Symptomatic central nervous system (CNS) metastases must have been treated, be
asymptomatic for ≥ 14 days, and meet the following criteria at the time of enrollment:
1. No concurrent treatment for CNS disease (e.g., surgery, radiation,
corticosteroids ≥ 10 mg prednisone per day or equivalent).
2. No concurrent leptomeningeal disease or spinal cord compression.
Key Exclusion Criteria:
- Participants with a history of known autoimmune disease with the exceptions of:
1. Vitiligo.
2. Psoriasis not requiring systemic treatment for > 1 year before receiving TAK-186.
3. History of Graves' disease in participants now euthyroid for > 4 weeks.
4. Hypothyroidism managed by thyroid replacement.
5. Alopecia.
6. Well-controlled diabetes type 1.
- Major surgery or traumatic injury within 8 weeks before first dose of TAK-186.
- Unhealed wounds from surgery or injury.
- Radiation therapy < 2 weeks before initiation of TAK-186.
- Treatment with > 10 mg per day of prednisone (or equivalent) or other
immune-suppressive drugs within the 7 days before the initiation of study drug.
Steroids for topical, ophthalmic, inhaled, or nasal administration are allowed.
- Prior therapy within the following timeframe before the planned start of TAK-186 as
follows:
1. Cytotoxic chemotherapy, small molecule inhibitors, radiation, interventional
radiology procedure, or similar investigational therapies: ≤ 2 weeks or 5
half-lives, whichever is shorter.
2. Monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or
similar investigational therapies: ≤ 4 weeks.
3. Concurrent use of hormones either to maintain castrate levels of testosterone in
participants with castration-sensitive prostate cancer or for non-cancer-related
conditions (e.g., insulin for diabetes, hormone replacement therapy) is
acceptable. Bisphosphonates are permitted for supportive care of bone metastases
(e.g., breast or prostate cancer) or osteoporosis.
- Clinically significant cardiovascular or vascular disease including:
1. Myocardial infarction or unstable angina < 6 months before the initiation of
study drug.
2. Clinically significant cardiac arrhythmia (e.g., with potential for hemodynamic
instability).
3. Uncontrolled hypertension: systolic blood pressure > 180 mmHg; diastolic blood
pressure > 100 mmHg.
4. Pulmonary embolism, stroke, or transient ischemic attack < 6 months before
initiation of TAK-186.
5. QTcF (QT interval by Fridericia correction) prolongation > 480 msec.
6. Congestive heart failure (New York Heart Association Class III or IV).
7. Pericarditis or clinically significant pericardial effusion.
8. Myocarditis.
9. Vasculitis not resolved < 6 months before TAK-186 initiation.
- Clinically significant gastrointestinal disorders including:
1. Gastrointestinal perforation < 6 months before study drug administration.
Participants must have documented evidence (e.g., upper endoscopy, colonoscopy)
of completely healed area of prior perforation.
2. Gastrointestinal bleeding < 2 months before study drug administration.
Participants must have documented evidence (e.g., upper endoscopy, colonoscopy)
of completely healed area of prior bleeding.
3. Pancreatitis < 6 months before the initiation of study drug. Participants must
have a CT scan negative for evidence of remaining disease or normal pancreatic
enzyme levels for > 4 weeks before the initiation of TAK-186.
4. Diverticulitis flare < 2 months before study drug administration. Participants
must have a CT scan negative for evidence of remaining disease before the
initiation of TAK-186.
5. History of Crohn's disease or ulcerative colitis.
- Inflammatory process that has not resolved for ≥ 4 weeks from the date of first study
dose. Participants with chronic low-grade inflammatory processes such as
radiation-induced pneumonitis are excluded regardless of duration.
- Clinically significant pulmonary compromise (e.g., requirement for supplemental oxygen
on a continuous basis).
- Active viral, bacterial, or systemic fungal infection requiring parenteral treatment
within 7 days before the initiation of study drug. Systemic antiviral, antifungal, or
antibacterial therapy must be completed > 1 week before the initiation of study drug.
Antimicrobial prophylaxis (e.g., for Pneumocystis carinii infection) may continue the
antimicrobial for that purpose.
- Vaccination with any live virus vaccine within 4 weeks before the initiation of study
drug administration or vaccination with other vaccines 2 weeks before the initiation
of study drug administration. Inactivated annual influenza vaccination is allowed.
- Participants who are known to be human immunodeficiency virus positive or who are
known to be hepatitis B or C positive. Participants treated for hepatitis C must have
viral titers of 0 for ≥ 2 years to be eligible. Participants with hepatitis B having
undetectable or ≤ 500 IU hepatitis B viral titers are eligible. Participants with
hepatocellular carcinoma (HCC) known history of hepatitis B are excluded, regardless
of hepatitis B viral titers.
- Second primary invasive malignancy not in remission for ≥ 3 years. Exceptions include
non-melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer
(Gleason score ≤ 7), resected melanoma in situ, or any malignancy considered to be
indolent and never having required therapy, excluding indolent lymphoid malignancies.
- Any serious underlying medical or psychiatric condition that would preclude
understanding and rendering of informed consent or impair the ability of the
participant to receive or tolerate the planned treatment.
- Known hypersensitivity to TAK-186 (or any excipient [trehalose, histidine, arginine,
or polysorbate-80] contained in the drug or diluent formulation) known
hypersensitivity to tocilizumab.
- Investigative site personnel or sponsor personnel directly affiliated with this study
or known hypersensitivity to tocilizumab.
- Prisoners or other individuals who are involuntarily detained.
- Any medical or non-medical issue that would contraindicate the participant's
participation in the study or confound the results of the study.
- Female participants who are breastfeeding.