Enapotamab Vedotin (HuMax-AXL-ADC) Safety Study in Patients With Solid Tumors

• ClinicalTrials.gov Identifier: NCT02988817
• Recruitment Status: Completed
• First Posted: December 9, 2016
• Last Update Posted: December 9, 2021
• Sponsor: Genmab
• Information provided by (Responsible Party): Genmab

Tracking Information

• First Submitted Date: December 1, 2016
• First Posted Date: December 9, 2016
• Last Update Posted Date: December 9, 2021
• Actual Study Start Date: December 2016
• Actual Primary Completion Date: November 12, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 3, 2021)

• Dose Limiting Toxicities (DLTs) [ Time Frame: Dose Limiting Toxicities will be assessed from first treatment cycle (3 or 4 weeks) ]
  As this is a phase I trial the main objective is to assess the recommended phase 2 dose of enapotamab vedotin (HuMax-AXL-ADC)
• Adverse events (AEs) [ Time Frame: AEs are collected throughout trial until the end of the safety follow-up period (30 days after last dose)] To access the safety and tolerability of enapotamab vedotin (HuMax-AXL-ADC) throughout the treatment periods of patients participating in the trial ]
  As this is a phase I trial the main objective is to assess the safety and tolerability of enapotamab vedotin (HuMax-AXL-ADC) throughout the treatment periods of the patients participating in the trial.

Original Primary Outcome Measures (submitted: December 8, 2016)

• Dose Limiting Toxicities (DLTs) [ Time Frame: Dose Limiting Toxicities will be assessed from first treatment cycle (3 or 4 weeks) ]
  As this is a phase I trial the main objective is to assess recommended phase 2 dose of HuMax-AXL-ADC
• Adverse events (AEs) [ Time Frame: At end of trial (up to 24 months) ]
  As this is a phase I trial the main objective is to assess the safety and tolerability of HuMax-AXL-ADC throughout the treatment periods of the patients participating in the trial.

Current Secondary Outcome Measures (submitted: December 3, 2021)

• Number of patients with treatment-emergent adverse events as assessed by CTCAE v.4.03 [ Time Frame: Through study completion, an average of 1 year ]
  Evaluate safety and tolerability of enapotamab vedotin based on treatment-emergent adverse events (including serious adverse events), clinical laboratory parameters, ECGs and vital signs
• Pharmacokinetics (PK): Maximum plasma concentration (Cmax) of enapotamab vedotin [ Time Frame: Approximately 12 months. As of Amendment 10 this is no longer being assessed ]
  Plasma concentrations of GEN1021
• Pharmacokinetics (PK): Area under the plasma concentration-time curve (AUC) of enapotamab vedotin [ Time Frame: Approximately 12 months. As of Amendment 10 this is no longer being assessed ]
  Plasma concentrations of GEN1021
• Pharmacokinetics (PK): Time to reach maximum plasma concentration (Tmax) of enapotamab vedotin [ Time Frame: Approximately 12 months. As of Amendment 10 this is no longer being assessed ]
  Plasma concentrations of GEN1021
• Pharmacokinetics (PK): Terminal elimination half-life (T1/2) of enapotamab vedotin and free toxin (MMAE) [ Time Frame: Approximately 12 months. As of Amendment 10 this is no longer being assessed ]
  Plasma concentrations of GEN1021
• Pharmacokinetics (PK): Minimum plasma concentration before administration (Cmin) of enapotamab vedotin [ Time Frame: Approximately 12 months. As of Amendment 10 this isno longer being assessed ]
  Plasma concentrations of GEN1021
• Pharmacokinetics (PK): Volume of distribution and AUC (R) of enapotamab vedotin [ Time Frame: Approximately 12 months. As of Amendment 10 this is no longer being assessed ]
  Plasma concentrations of GEN1021
• Pharmacokinetics (PK): Plasma clearance of enapotamab vedotin [ Time Frame: Approximately 12 months. As of Amendment 10 this is no longer being assessed ]
  Plasma concentrations of GEN1021
• Percentage of participants With Anti- enapotamab vedotin Antibodies [ Time Frame: From baseline through 12 months. As of Amendment 10, this is no longer being assessed ]
  Percentage of participants with treatment-emergent positive anti-GEN1021 antibodies by treatment group.
• CA-125 response rate [ Time Frame: From baseline through 12 months. As of Amendment 10, this is no longer being assessed ]
  Response will be defined according to GCIG criteria which require a reduction of CA-125 of > 50% relative to pre-treatment CA-125 level, maintained for at least 28 days
• Best PSA response during treatment as an absolute change relative to baseline [ Time Frame: Through treatment completion: approximately 12 months ]
• Objective Response Rate (ORR) in Part 2 [ Time Frame: Approximately 12 months ]
  Proportion of patients who have achieved a PR or complete response (CR) according to RECIST 1.1
• Progression-free survival (PFS) [ Time Frame: Approximately 12 months ]
  PFS is defined as the time from date of first dose to objectively documented progression of disease or death
• Duration of response (DOR) [ Time Frame: Approximately 12 months ]
  DOR is defined as the length of time between first response and the date of objectively documented progression of disease or death
• Overall survival (OS [ Time Frame: Approximately 24 months ]
  OS is defined as the length of time between first dose to death.
• Investigation on biomarkers associated with the clinical efficacy [ Time Frame: Time Frame: through treatment completion: approximately 12 months. As of Amendment 10, this no longer be assessed ]
  Using immunohistochemistry (IHC) method to measure and score Axl expression in tumor tissue samples collected at screening, during treatment and at the end of treatment.

Original Secondary Outcome Measures (submitted: December 8, 2016)

• Pharmacokinetic (PK) parameters, Cmax [ Time Frame: At end of trial (up to 10 months) ]
• Anti-tumor activity measured by tumor shrinkage (based on computerized tomography [CT]-scan evaluations), change in Cancer Antigen (CA) 125. [ Time Frame: At end of trial (up to 12 months) ]
• Pharmacokinetic (PK) parameters, AUC [ Time Frame: At end of trial (up to 10 months) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Enapotamab Vedotin (HuMax-AXL-ADC) Safety Study in Patients With Solid Tumors
• Official Title: 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
• 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 two dose escalation arms: the first arm investigates a once every 3 weeks (1Q3W) dosing schedule and the second arm investigates a three administrations over 4 weeks (3Q4W) dosing schedule.

The Expansion part of the trial will further explore the recommended phase 2 dose and dosing regimens of HuMax-AXL-ADC as determined in Part 1

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Ovarian Cancer
• Cervical Cancer
• Endometrial Cancer
• Non Small Cell Lung Cancer
• Thyroid Cancer
• Melanoma
• Sarcoma

Intervention

Biological: Enapotamab vedotin (HuMax-AXL-ADC)

All arms of the trial (both in escalation and expansion phase) will be administered enapotamab vedotin (HuMax-AXL-ADC)

Study Arms

Experimental: Enapotamab vedotin (HuMax-AXL-ADC)

All arms of the trial (both in escalation and expansion phase) will be administered enapotamab vedotin (HuMax-AXL-ADC)

Intervention: Biological: Enapotamab vedotin (HuMax-AXL-ADC)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 3, 2021): 306
• Original Estimated Enrollment (submitted: December 8, 2016): 165
• Actual Study Completion Date: November 12, 2021
• Actual Primary Completion Date: November 12, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. For the dose escalation part: Patients with selected, relapsed solid tumors who have failed available standard therapy or who are not candidates for standard therapy.
2. For the expansion part: Patients with relapsed, advanced and/or metastatic solid tumors who are not candidates for standard therapy
3. Patients must have measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST).
4. For the expansion patients must provide a fresh tumor biopsy at enrolment
5. Age ≥ 18 years.
6. Acceptable renal function
7. Acceptable liver function
8. Acceptable hematological status
9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
10. Life expectancy of at least three months.
11. 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
12. Patients must provide a signed informed consent form before any trial relates activities are carried out.

Exclusion Criteria:

1. Acute deep vein thrombosis or clinically relevant pulmonary embolism, not stable for at least 4 weeks prior to first IMP administration.
2. Have clinically significant cardiac disease
3. 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.
4. Uncontrolled hypertension
5. Have received granulocyte colony stimulating factor (G-CSF) or granulocyte/macrophage colony stimulating factor support 3 weeks prior to first IMP administration.
6. 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.
7. 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.
8. Major surgery within four weeks before first IMP administration.
9. Any history of intracerebral arteriovenous malformation, cerebral aneurysm, brain metastases or stroke.
10. 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.
11. Prior therapy with a conjugated or unconjugated auristatin derivative/vinca-binding site targeting payload.
12. Radiotherapy within 14 days prior to first IMP administration.

13. 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.
14. Melanoma patients with an LDH ≥ 3 x ULN.

15. Ongoing significant, uncontrolled medical condition including:

    o Serious, non-healing wound, skin ulcer (of any grade), or bone fracture.

16. Grade 2 or higher peripheral neuropathy.
17. Clinically significant active viral, bacterial or fungal infection
18. Known human immunodeficiency virus seropositivity.
19. Known positive serology for hepatitis B (unless due to vaccination or passive immunization due to immunoglobulin therapy)
20. Known positive serology for hepatitis C (unless due to immunoglobulin therapy)
21. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the trial or evaluation of the trial result
22. 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 IMP
23. Body weight < 40 kg
24. Women who are pregnant or breast feeding.
25. Pulmonary hemorrhage or hemoptysis > 2.5 ml blood within 6 weeks unless cause has been addressed and is medically resolved.
26. History of acute pneumonitis.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Denmark, Netherlands, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT02988817
• Other Study ID Numbers: GCT1021-01
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Genmab
• Original Responsible Party: Same as current
• Current Study Sponsor: Genmab
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Ignace Vergote, Professor; Universitair Ziekenhuizen Leuven

• PRS Account: Genmab
• Verification Date: November 2021