MC# 17-36 - First-in-Human, Open-Label, Dose-Escalation Trial with Expansion Cohorts to Evaluate Safety of Axl-Specific Antibody-Drug Conjugate (enapotamab vedotin,HuMax®-AXL-ADC) in Patients with Solid Tumors
Disease Type(s): Bladder, Breast, Cervical, Colorectal, Endometrial, Esophageal, Gastric, Head and Neck, Hepatocellular, Mesothelioma, Neuroendocrine, Pancreatic, Prostate, Thyroid, Renal, Lung-NSCLC, Cholangiocarcinoma, Nasopharyngeal
Drug Classification(s): Targeted Therapy, Immunotherapy, Monoclonal Antibody
Molecular Target(s): AXL
Mechanism of Action
GCT1021 (HuMax-AXL-ADC) is a human IgG1 antibody that is generated by conjugation of an Axl-specific antibody with a tubulin inhibitor (MMAE). HuMax-AXL-ADC binds to the Ig1 domain of Axl and induces tumor cell killing by MMAE-mediated interference of cell division. Axl overexpression has been associated with resistance to kinase inhibitors.
In this study, the sponsor and investigators want to learn:
- The safety and tolerability of HuMax-AXl-ADC
- How much HuMax-AXl-ADC is absorbed into the blood and how fast it is removed
- If research tests can be used in the future to predict who will benefit from HuMax-AXl-ADC
- How proteins that indicate the status of disease are affected with use of HuMax-AXl-ADC
- For the expansion part: Patients with advanced and/or metastatic solid tumors who are not candidates for standard therapy , and for whom, in the opinion of the investigator, experimental therapy with enapotamab vedotin may be beneficial.
- Patients must have measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST).
- For the expansion patients must provide a fresh tumor biopsy at enrollment
- Age ≥ 18 years.
- Acceptable renal function
- Acceptable liver function
- Acceptable hematological status
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Life expectancy of at least three months.
- Patients, both females and males, of childbearing/reproductive potential must agree to use adequate contraception while included in the trial and for six months after the last infusion of enapotamab vedotin
- Patients must provide a signed informed consent form before any trial relates activities are carried out.
- Acute deep vein thrombosis or clinically relevant pulmonary embolism, not stable for at least 4 weeks prior to first enapotamab vedotin administration.
- Patient has a history of thromboembolic event(s) and is not willing to take thromboembolic prophylaxis.
- Have clinically significant cardiac disease
- Onset of unstable angina within six months of signing ICF
- Acute myocardial infarction within six months of signing ICF
- Known congestive heart failure (Grade III or IV as classified by the New York Heart Association); and/or a known decreased cardiac ejection fraction of <45% and/or baseline QT interval as corrected by Fridericia’s formula (QTcF) > 480 msec or uncontrolled atrial fibrillation.
- Uncontrolled hypertension defined as systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg, despite optimal medical management
- Ongoing or recent (within 1 year) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk for immune related adverse events
- Patients with a history of Grade 3 or higher immune related adverse events should be excluded (adverse events below Grade 3 should be discussed with the sponsor).
- Patients with ongoing pneumonitis at screening or with a history of non-infectious pneumonitis that required steroids.
- Have received granulocyte colony stimulating factor (G-CSF) or granulocyte/macrophage colony stimulating factor support 3 weeks prior to first enapotamab vedotin administration.
- Have received a cumulative dose of corticosteroid ≥ 150 mg prednisone (or equivalent doses of corticosteroids) within two weeks before the first enapotamab vedotin administration.
- History of ≥ grade 3 allergic reactions to monoclonal antibody therapy as well as known or suspected allergy or intolerance to any agent given in the course of this trial.
- Major surgery within four weeks before first enapotamab vedotin administration.
- Any history of intracerebral arteriovenous malformation, cerebral aneurysm, brain metastases or stroke.
- Any anticancer therapy including; small molecules, immunotherapy, chemotherapy monoclonal antibodies or any other experimental drug within five half-lives but maximum four weeks before first infusion. Accepted exceptions are bisphosphonates, denosumab and gonadotropin-releasing hormone agonist or antagonist.
- Any prior therapy with a conjugated or unconjugated auristatin derivative/vinca-binding site targeting payload (Previous treatment with vinca alkaloids is allowed in line with inclusion criterion #1).
- Radiotherapy within 14 days prior to first enapotamab vedotin administration.
- Known past or current malignancy other than inclusion diagnosis, except for:
- Cervical carcinoma of Stage 1B or less.
- Non-invasive basal cell or squamous cell skin carcinoma.
- Non-invasive, superficial bladder cancer.
- Prostate cancer with a current PSA level < 0.1 ng/mL.
- Breast cancer in BRCA1 or BRCA2 positive ovarian cancer patients.
- Any curable cancer with a complete response (CR) of > 2 years duration.
- Melanoma patients with an LDH ≥ 3 x ULN.
- Ongoing significant, uncontrolled medical condition including:
- Serious, non-healing wound, skin ulcer (of any grade), or bone fracture
- Grade 2 or higher peripheral neuropathy.
- Clinically significant active viral, bacterial or fungal infection
- Known human immunodeficiency virus seropositivity.
- Known positive serology for hepatitis B (unless due to vaccination or resolved natural infection or unless passive immunization due to immunoglobulin therapy)
- Known positive serology for hepatitis C (unless due to immunoglobulin therapy)
- Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the trial or evaluation of the trial result
- History of organ allograft (except for corneal transplant) or autologous or allogeneic bone marrow transplant, or stem cell rescue within 3 months prior to the first dose of enapotamab vedotin
- Body weight < 40 kg
- Women who are pregnant or breast feeding.
- Patients are not allowed to take part in any other interventional trial while participating in current trial.
- Pulmonary hemorrhage or hemoptysis > 2.5 ml blood within 6 weeks unless cause has been addressed and is medically resolved.
- History of acute pneumonitis.
- Dallas, TX - Mary Crowley Cancer Research - Medical City