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
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- Ovarian Cancer
- Sponsor
- Genmab
- Enrollment
- 306
- Locations
- 41
- Primary Endpoint
- Number of Participants With Grade 3 or 4 Laboratory Results
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
The purpose of the trial is to determine the maximum tolerated dose and to establish the safety profile of HuMax-AXL-ADC in a mixed population of patients with specified solid tumors
Detailed Description
The trial consists of two parts; a dose escalation part (phase I, first in-human (FIH)) and an expansion part (phase IIa). The dose escalation part has 2 dosing schedules: 1 dose every 3 weeks (1Q3W) dose regimen, and 3 doses every 4 weeks (3Q4W) dosing regimen. The Expansion part of the trial will further explore the recommended phase 2 dose and dosing regimens of HuMax-AXL-ADC as determined in dose escalation part.
Investigators
Eligibility Criteria
Inclusion Criteria
- •For the dose escalation part: Patients with selected, relapsed or refractory solid tumors who have failed available standard therapy or who are not candidates for standard therapy. For the expansion part: Patients with advanced and/or metastatic solid tumors who are not candidates for standard therapy
- •Patients must have measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST).
- •For the expansion patients must provide a tumor tissue sample from archival tissue or fresh biopsy at enrolment
- •Age ≥ 18 years.
- •Acceptable renal function
- •Acceptable liver function
- •Acceptable hematological status
- •Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •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 HuMax-AXL-ADC
Exclusion Criteria
- •Acute deep vein thrombosis or clinically relevant pulmonary embolism, not stable for at least 4 weeks prior to first IMP administration.
- •Have clinically significant cardiac disease
- •Known congestive heart failure and/ or a known decreased cardiac ejection fraction of \< 45%. A baseline QT interval as corrected by Fridericia's formula (QTcF) \> 480 msec, a complete left bundle branch block (defined as a QRS interval ≥ 120 msec in left bundle branch block form) or an incomplete left bundle branch block.
- •Uncontrolled hypertension
- •Have received granulocyte colony stimulating factor (G-CSF) or granulocyte/macrophage colony stimulating factor support 3 weeks prior to first IMP administration.
- •Have received a cumulative dose of corticosteroid \> 150 mg prednisone (or equivalent doses of corticosteroids) within two weeks before the first Investigational Medicinal Product (IMP) 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 IMP 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.
Outcomes
Primary Outcomes
Number of Participants With Grade 3 or 4 Laboratory Results
Time Frame: Day 1 through Day 1130 (maximum observed duration)
Number of participants with laboratory measurements graded as Grade 3 or 4 by NCI-CTCAE v 4.03 is reported.
Number of Participants With Dose-limiting Toxicities (DLTs) for Dose-escalation Part
Time Frame: From Day 1 to Day 21 of first cycle for 1Q3W dosing regimen and from Day 1 to Day 28 of first cycle for 3Q4W dosing regimen
The DLTs were defined as Grade (G) 4 neutropenia or G4 thrombocytopenia for a minimal duration of 7 days, G3 and G4 febrile neutropenia, \>=G3 hemorrhage associated with \>=G3 thrombocytopenia, G4 anemia; Stevens Johnson syndrome, toxic epidermal necrolysis, \>=G3 cutaneous vasculitis; G3 neuropathy (not improved to G1 within 3 weeks following pausing of dosing) and G4 neuropathy; G3 infusion-related reactions (IRR) that did not resolve to G1 or baseline within 24 hours; G4 IRR or G4 anaphylaxis events; \>= G3 diarrhoea and/or vomiting persisting \>48 hours or G3 nausea lasting 7 days (both despite optimal medical management); or any \>=G3 related non-hematological AEs, which occurred during the Cycle 1 and regarded as medically important as assessed by the Data Monitoring Committee (excluding Grade 3 fatigue or non-hematological laboratory abnormalities as specified in protocol).
Number of Participants With >= Grade 3 TEAEs as Assessed by National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03
Time Frame: Day 1 through Day 1130 (maximum observed duration)
Number of participants with TEAEs of \>= Grade 3 as assessed by NCI-CTCAE v4.03 is reported. The NCI-CTCAE is a descriptive terminology is used for AE reporting. The NCI-CTCAE v4.03 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE, based on this general guideline: Grade 1 as mild AE, Grade 2 as moderate AE, Grade 3 as severe AE, Grade 4 as life-threatening or disabling AE, and Grade 5 as death. If a participant reported multiple severity grades for an AE, only the maximum grade was used.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
Time Frame: Day 1 through Day 1130 (maximum observed duration)
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is defined as an AE that meets one of the following criteria: requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, is a congenital anomaly/birth defect, is medically important, results in death, or is life-threatening. In this trial, a TEAE was defined as an AE occurring or worsening between the first dose of enapotamab vedotin and 30 days after the last dose received.
Number of Participants With Treatment-emergent Infusion-related AEs and TEAEs Related to Enapotamab Vedotin
Time Frame: Day 1 through Day 1130 (maximum observed duration)
Number of participants with treatment-emergent infusion-related AEs and TEAEs related to enapotamab vedotin is reported.
Secondary Outcomes
- AUC0-last of MMAE for 1Q3W Dose-escalation Part(Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3)
- Tmax of MMAE for Dose-escalation Part(For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3)
- Total Clearance (CL) of Conjugated Enapotamab Vedotin in Dose-escalation Part(For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3)
- Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Conjugated Enapotamab Vedotin for 1Q3W Dose-escalation Part(Predose, end of infusion (EOI), and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3)
- Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Conjugated Enapotamab Vedotin for 1Q3W Dose-escalation Part(Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3)
- Half-life Lambda-z (t1/2) of Conjugated Enapotamab Vedotin for Dose-escalation Part(For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3)
- Cmax of MMAE for Dose-escalation Part(For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: Predose and EOI on Days 1 and 8 of Cycles 1 and 3; and predose, EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3)
- Number of Participants With Objective Response (OR) Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) As Assessed by Investigator(Day 1 through 44.5 months (maximum observed duration))
- Number of Participants With Best Cancer Antigen 125 (CA-125) Response(From Screening (within 2 weeks before starting of the study treatment) through Day 1130 (maximum observed duration))
- Overall Survival (OS)(Day 1 through 44.5 months (maximum observed duration))
- Change in AXL Expression (Total Tumor H-score) From Baseline to EOT Visit for Expansion Part(Baseline (Study Days -21 to 1) and EOT visit (Day 1100))
- Time of Maximum Plasma Concentration (Tmax) of Conjugated Enapotamab Vedotin for Dose-escalation Part(For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3)
- Volume of Distribution at Steady State (Vss) of Conjugated Enapotamab Vedotin for Dose-escalation Part(For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3)
- AUC0-inf of Free Toxin Monomethyl Auristatin E (MMAE) for 1Q3W Dose-escalation Part(Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3)
- Total CL of MMAE in Dose-escalation Part(For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3)
- Number of Participants With Antidrug Antibodies (ADAs) Confirmed Positive to Enapotamab Vedotin(Day 1 through Day 1130 (Dose-escalation part: Predose of Day 1 of Cycles 1 to 12, end of treatment [EOT], and 30 days after last study drug; Expansion part: Predose on Day 1 of Cycles 1 to 5, then every fourth cycle until PD))
- Duration of Response (DoR) Based on RECIST v1.1 as Assessed by Investigator for Expansion Part(Day 1 through 44.5 months (maximum observed duration))
- Progression Free Survival (PFS) as Assessed by Investigator(Day 1 through 44.5 months (maximum observed duration))
- Maximum Observed Plasma Concentration (Cmax) of Conjugated Enapotamab Vedotin for Dose-escalation Part(For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: Predose and EOI on Days 1 and 8 of Cycles 1 and 3; and predose, EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3)
- t1/2 of MMAE for Dose-escalation Part(For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3)