IRB Study Number 23-720
Status Recruiting
Institute Taussig Cancer Institute
Description
5.1.1 Primary Objective
• To characterize the safety, tolerability, and dose-limiting toxicities (DLTs) of TAK-280 to determine the maximum tolerated dose (MTD) (if any) and recommended phase 2 dose (RP2D).
5.1.2 Secondary Objectives
• To characterize the PK of TAK-280.
• To evaluate the preliminary antitumor activity of TAK-280 per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1.
• To evaluate the potential immunogenicity of TAK-280.
Inclusion Criteria
Age ≥18 years or ≥ the local legal age of majority, as applicable.
Criteria for disease state in dose escalation (2a) and cohort expansion (2b).
a. Tumor histologies during dose escalation: Dose escalation will begin by initially enrolling patients with histologically or pathologically confirmed unresectable, locally advanced or metastatic cancers that, based on literature reports, are considered to express B7-H3. Patients will be either ineligible for or intolerant of standard therapies, have no approved therapy with demonstrated benefit available, or have exhausted all available standard therapies.
Eighteen tumor types will be included for the initial dose-escalation cohorts, as follows:
• RCC.
• TNBC.
• Gastric or gastroesophageal adenocarcinoma.
• Esophageal squamous cell cancer.
• Skin squamous cell carcinoma.
• Pancreatic cancer.
• HCC.
• CRC.
• Epithelial OC.
• Cervical cancer.
• Endometrial adenocarcinoma.
• Thyroid cancer (follicular or papillary).
• NSCLC.
• SCLC.
• mCRPC.
• HNSCC.
• UC.
• Melanoma.
b. Tumor histologies during cohort expansion: Patients will be eligible if they have histologically proven, unresectable, locally advanced, or metastatic malignant neoplasms for which no standard therapy with demonstrated benefit is currently available, have exhausted all available approved therapies, or are ineligible for or intolerant of standard therapy, as follows:
• mCRPC: in patients who have received ≥2 but no more than 4 prior systemic therapies that are approved for the locally advanced or CRPC. At least 1 line must be a second-generation antiandrogen therapy (eg, abiraterone, enzalutamide, apalutamide, or darolutamide).
– Patients without prior surgical castration must continue receiving a gonadotropinreleasing hormone analog (agonist or antagonist) to maintain testosterone levels ≤50 ng/dL (≤1.75 nmol/L) during study treatment.
– Patients must have documented metastases on one of the following modalities: bone scanning, PSMA-PET, or CT/magnetic resonance imaging (MRI).
• Metastatic or advanced non-small-cell lung cancer (NSCLC):
– Patients with no known activating mutations: have received platinum-based chemotherapy and anti-PD/PDL-1 for the locally advanced or metastatic disease (chemotherapy and anti-PD/PDL-1 treatment can be received in combination or in sequence).
– Patients with a known activating mutation with an approved and accessible target therapy (including but not limited to EGFR, ALK, ROS1, BRAF V600, RET, MET exon 14 skipping mutation, NTRK, KRAS G12C) should have received the respective target therapy and 1 line of platinum-based chemotherapy and anti- PD1/PDL-1 (if appropriate).
– Patients should have received no more than 3 prior lines of therapies for locally advanced or metastatic cancer.
• Cutaneous melanoma
– Patients who have received prior anti-PD1/L1 and/or anti-CTLA-4 treatment,
– Patients who have BRAFm should have received prior BRAFi and/or MEKi treatment in addition.
– Patients should have received no more than 3 lines of prior therapy.
Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
Measurable disease per RECIST V1.1 by investigator except for patients with PC and only bone metastases (these patients are allowed in the study).
Acceptable laboratory parameters include the following:
• Albumin ≥3.0 g/dL.
• Platelet count ≥75×103/μL.
• Hemoglobin ≥9.0 g/dL.
• Absolute neutrophil count (ANC) ≥1.0×103/μL.
• ALT/AST ≤3.0× the upper limit of normal (ULN); for patients with hepatic metastases, ALT and AST ≤5× ULN.
• Total bilirubin ≤1.5 ULN, except patients with Gilbert’s syndrome, who may enroll if the conjugated bilirubin is within normal limits.
• Creatinine clearance ≥45 mL/minute (calculated by Cockcroft-Gault formula).
Archival tissue: Patients must consent to the acquisition of existing formalin-fixed paraffinembedded (FFPE) archival tumor sample, if available, either a block or unstained slides.
Tumor biopsy:
• Starting in the 6 μg/kg dose-cohort during dose escalation, patients are strongly encouraged to provide fresh tumor biopsy samples during screening (pretreatment) and within 7 days before C3D1 (on treatment), as specified in the SOE (Appendix A), when a lesion is safely accessible for a low-risk biopsy procedure (those occurring outside the brain, lung/mediastinum, and intra-abdominal space or accessible by endoscopic procedures beyond the stomach or bowel). If a pretreatment biopsy is not provided, on treatment biopsy is still strongly encouraged.
• During the cohort-expansion phase, similar paired tumor biopsies, preferably from the same lesion, will be required from patients at specific study sites. The requirement for a biopsy specimen may be removed if endpoint criteria are met (see Appendix I for statistical considerations for paired biopsy specimens). Patients with mCRPC limited to bone metastasis are exempt from this requirement.
• Tumor lesions used for biopsy should not be lesions used as one of the target lesions for response evaluation, unless there are no other lesions suitable for biopsy. Tumor biopsy samples should be obtained only from lesions that are thought to be accessible with acceptable clinical risk in the judgment of the investigator. The sponsor should be
contacted if biopsy is considered to present a potentially unreasonable risk to the patient. See Section 9.4.16.2 for additional guidance for tumor biopsies.
- Female patients of childbearing potential (not surgically sterilized and between menarche and 1 year after menopause) must meet the following criteria:
• Have a negative serum or urine pregnancy test result within 72 hours before the initiation of study drug administration.
• Be willing to use 2 forms of effective contraception throughout the study, starting with the screening and through 90 days after the last dose of TAK-280. Examples of effective contraception are birth control pills, birth control patch (eg, Ortho Evra), NuvaRing, intrauterine device, female condom, diaphragm with spermicide, cervical cap, use of a condom by the sexual partner, documented sterility of a sexual partner or documented evidence of surgical sterilization at least 6 months before screening (eg, bilateral tubal ligation or hysterectomy).
• Practice abstinence, if this is the established and preferred contraception method for the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.).
- Male patients with partners of childbearing potential, even if surgically sterilized (ie, status post vasectomy) must agree to the following:
• Use effective barrier contraception from the time of consent through 90 days after the last dose of TAK-280, or
• Agree to practice true abstinence, if this is the established and preferred contraception method by the patient (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.).
• In addition, have their partners use contraception (as documented for female patients) for the same period of time.
• Male patients must agree to refrain from donating sperm from the time of consent through 90 days after the last dose of TAK-280.
- 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:
• No concurrent treatment for CNS disease (eg, surgery, radiation, corticosteroids ≥10 mg/d prednisone or equivalent).
• No concurrent leptomeningeal disease or cord compression.
- Patients must be willing and able to comply with clinic visits and procedures outlined in the study protocol.
Exclusion Criteria
- History of known autoimmune disease with the exception of the following:
• Vitiligo.
• Psoriasis not requiring systemic treatment for >1 year before receipt of TAK-280.
• History of Graves disease in patients now euthyroid for >4 weeks.
• Hypothyroidism managed by thyroid replacement.
• Alopecia.
• Well-controlled diabetes type 1.
Major surgery or traumatic injury within 8 weeks before first dose of TAK-280.
Baseline prolongation of the QT interval with Fridericia correction method (QTcF) (eg, repeated demonstration of corrected QT interval (QTc) >480 ms, history of congenital long QT syndrome, or torsades de pointes). If patients are taking medications known to prolong the QTc (examples provided in Appendix G) at screening, patients may continue to take these medications as long as their baseline QTcF is <480 ms while receiving such medications. Patients may not start using such medications on C1D1. Please refer to Section 8.6 (Permitted Concomitant Medications and Procedures) for more details.
Unhealed wounds from surgery or injury.
Ongoing or active infection of Grade ≥2.
History of any of the following ≤6 months before the first dose:
• Congestive heart failure New York Heart Association Grade III or IV (Appendix H).
• Unstable angina.
• Myocardial infarction.
• Unstable symptomatic ischemic heart disease.
• Uncontrolled hypertension despite appropriate medical therapy.
• Any ongoing symptomatic cardiac arrhythmias of Grade >2 (including acute atrial flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia).
• Pulmonary embolism, or symptomatic cerebrovascular events, or any other serious cardiac condition (eg, pericardial effusion or restrictive cardiomyopathy).
• Chronic, stable atrial fibrillation on stable anticoagulant therapy, including lowmolecular-weight heparin, is allowed.
Oxygen saturation <92% on room air at screening or during the C1D1 predose assessment.
Inflammatory process that has not resolved for ≥4 weeks before the first dose of study drug. Patients with chronic low-grade inflammatory processes such as radiation-induced pneumonitis are excluded regardless of duration.
Clinically significant gastrointestinal disorders including the following:
• Gastrointestinal perforation or unhealed ulcerations <6 months before study drug administration. Patients must have documented evidence (eg, upper endoscopy, colonoscopy) of a completely healed area of prior perforation.
• Gastrointestinal bleeding <2 months before study drug administration. Patients must have documented evidence (eg, from upper endoscopy or colonoscopy) of a completely healed area of prior bleeding.
• Pancreatitis <6 months before the initiation of study drug. Patients must have a CT scan that is negative for evidence of remaining disease or normal pancreatic enzyme levels >4 weeks before the initiation of TAK-280.
• Diverticulitis flare <2 months before study drug administration. Patients must have a CT scan demonstrating no evidence of remaining disease before the initiation of TAK-280.
• History of Crohn disease or ulcerative colitis.
Vaccination with any live virus vaccine within 4 weeks or other vaccines within 2 weeks before the initiation of study drug administration. Inactivated annual influenza vaccination is allowed.
History of a bone marrow transplantation within the past 5 years or solid organ transplantation (recipient) and use of immunosuppressive agents.
Known hypersensitivity to TAK-280 or any excipient (trehalose, histidine, arginine, poloxamer 188, or PS80) contained in the drug or diluent formulation, or known hypersensitivity to tocilizumab.
Second primary invasive malignancy not in remission for ≥3 years. Exceptions include nonmelanoma skin cancer, cervical carcinoma in situ, resected melanoma in situ, or any malignancy considered to be indolent and never required therapy, with the exception of indolent lymphomas.
Any serious underlying medical or psychiatric condition that would preclude informed consent or impair the ability of the patient to receive or tolerate the planned treatment or comply with the protocol.
Patients who are known to be HIV positive or who are known to be hepatitis B or hepatitis C positive. Patients treated for hepatitis C must have viral titers of 0 for ≥2 years to be eligible. Patients with hepatitis B who have undetectable or ≤500 IU hepatitis B viral titers are eligible.
Prior therapy within the following time frames before the planned start of TAK-280, as follows:
• Cytotoxic chemotherapy, small-molecule inhibitors, radiation, interventional radiology procedure, or similar investigational therapies: ≤2 weeks or 5 half-lives, whichever is shorter.
• Monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or similar therapies: ≤4 weeks.
• Not recovered to Grade 1 or baseline or established as sequelae from all toxic effects of previous therapy (except alopecia, neuropathy, or autoimmune endocrinopathies with stable endocrine replacement therapy, or bone marrow parameters [any of Grade ½ permitted if directly related to bone marrow involvement]).
• Concurrent use of hormones to maintain castrate levels of testosterone in patients with PC or use for noncancer-related conditions (eg, insulin for diabetes, hormone replacement therapy) is acceptable. Bisphosphonates are permitted for supportive care of patients with bone metastases (eg, breast cancer or PC).
- Use of corticosteroids or other immunosuppressive medication, concurrently or within 14 days of administration of TAK-280, with the following exceptions:
• Topical, intranasal, inhaled, ocular, or intra-articular corticosteroids.
• Physiologic doses of replacement steroid (eg, for adrenal insufficiency).
• Steroid premedication for hypersensitivity reactions and antiemetic use.
• Stable steroid dose (established for ≥28 days before the first dose of TAK-280) for previously treated brain metastasis. Corticosteroid dose on C1D1 should be ≤10 mg/d of prednisone or equivalent.
- Female patients who are lactating and breastfeeding or have a positive serum pregnancy test result during the screening period or a positive urine pregnancy test result on Day 1 before first dose of study drug.
