Clinical Trials

Inclusion Criteria:

• For the dose escalation part
  • Patients with relapsed or refractory cancer of the ovary, cervix, endometrium, thyroid, NSCLC, or melanoma (cutaneous, mucosal, acral or uveal melanoma) who have failed available standard therapy or who are not candidates for standard therapy, and for whom, in the opinion of the investigator, experimental therapy with enapotamab vedotin may be beneficial.
  • For the expansion part
    • Patients with advanced and/or metastatic cancer who are not candidates for standard therapy, and for whom, in the opinion of the investigator, experimental therapy with enapotamab vedotin may be beneficial, who have failed the following anticancer therapy as follows:
  • Expansion Cohort 1 (NSCLC patients with classical sensitizing EGFR mutations and/or EGFR mutations targeted by third generation TKIs [e.g., T790M for osimertinib])
    • NSCLC patients after failure of up to 4 prior treatment regimens containing systemic therapy for metastatic disease adjuvant and maintenance treatment is considered being part of one treatment regimen;
    • Documented progressive disease on last prior treatment;
    • Last prior treatment to enrolment to GCT1021-01 should have been an EGFR inhibitor (e.g., Erlotinib, Osimertinib, etc.) or a PD-1/PD-L1 inhibitor or a platinum-based doublet chemotherapy.
  • Expansion Cohort 2 (NSCLC patients without activating EGFR mutations or ALK rearrangements)
    • NSCLC patients after failure of no more than 2 lines of therapy which should include a platinum based chemotherapy and PD-1/PD-L1 inhibitor treatment for advanced (Stage IIIA or IIIB) or metastatic disease (Stage IV) either in combination or sequentially;
    • Documented progressive disease on last prior treatment;
    • Last prior treatment to enrolment to GCT1021-01 should have been (either in combination or sequentially) a platinum based chemotherapy or a PD-1/PD-L1 inhibitor.
  • Expansion Cohort 3 (Melanoma patients with BRAF V600 mutation)
    • Cutaneous, acral, or mucosal melanoma patients after failure of up to 4 prior treatment regimens containing systemic therapy for metastatic disease adjuvant and maintenance treatment is considered being part of one treatment regimen;
    • Documented progressive disease on last prior treatment;
    • Last prior treatment to enrolment to GCT1021-01 should have been a BRAF inhibitor (+/- Mek inhibitor) or a checkpoint inhibitor.
  • Expansion Cohort 4 (Melanoma patients with BRAF V600 wild-type)
    • Cutaneous, acral, or mucosal melanoma patients after failure of up to 3 prior treatment regimens containing systemic therapy for metastatic disease adjuvant and maintenance treatment is considered being part of one treatment regimen;
    • Documented progressive disease on last prior treatment;
    • Last prior treatment to enrolment to GCT1021-01 should have been a checkpoint inhibitor.
  • Expansion Cohort 5 (Sarcoma patients)
    • Sarcoma patients after failure of up to 3 prior treatment regimens containing systemic therapy for metastatic disease;
    • Limited to undifferentiated pleomorphic sarcoma, lipo-, leiomyosarcoma, synovial sarcoma, Ewing’s sarcoma, osteo-, and chondrosarcoma adjuvant and maintenance treatment is considered being part of one treatment regimen;
    • Documented progressive disease on last prior treatment.
  • Expansion Cohort 6 (patients with solid tumors, excluding NSCLC, melanoma, ovarian cancer, and sarcoma patients unless having a known AXL gene amplification; preferably no more than 8 patients should be recruited for one tumor type)
    • Patients with solid tumors (except for NSCLC, melanoma, ovarian cancer, and sarcoma patients unless having a known AXL gene amplification) that have failed a PD-1/PD-L1 inhibitor for metastatic disease;
    • Documented progressive disease on last prior treatment;
    • Last prior treatment to enrolment to GCT1021-01 should have been:
      • An immune checkpoint inhibitor.
  • Expansion Cohort 7 (Platinum-resistant ovarian cancer patients)
    • Ovarian cancer patients with resistance to at least one platinum-based therapy defined according to GCIG. Disease progression during or within 6 months of previous platinum based chemotherapy include the following 2 categories:
      • Primary platinum-resistant: Previously untreated patients who have achieved at least a partial response to platinum-based chemotherapy, but experience a relapse within a period of > 1 and < 6 months following treatment completion;
      • Secondary platinum-resistant: Previously treated patients who have achieved at least a partial response with platinum-based therapy as 2nd line treatment, but experience a relapse within a period of > 1 and < 6 months following treatment completion.
    • Ovarian cancer patients after failure of at least 2 prior treatment regimens containing systemic therapy but not more than 5 for recurrent disease.
    • Limited to invasive epithelial tubo-ovarian carcinoma including malignant serous (restricted to high-grade serous ovarian cancer (HGSOC), carcinosarcoma, and High Grade (or ≥ Grade 3) clear cell / endometrioid / mixed epithelial carcinoma.
    • Maintenance treatment (e.g., with bevacizumab, PARPi, PD-1/PD-L1 inhibitor, etc.) is considered being part of one treatment regimen.
    • Treatments that had to be changed to a similar drug due to toxicity count as one regimen (e.g., change from carboplatin to cisplatinum because of allergy, etc.).
    • Documented progressive disease on or after last prior treatment.
    • Start of screening must be within 60 days after documented progression.
    • Isolated GCIG CA 125 progression does NOT qualify for trial entry.
    • Albumin levels should be > 25 g/L (‘CTCAE G2 intermediate’) to allow inclusion.
  • For the following conditions in Expansion Cohorts 1-7, the sponsor medical officer’s approval of enrolment is needed:
    • if documented progression has not been on measurable disease (i.e., symptomatic progression).
• Patients must have measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1:
  • A minimum of one lesion ≥ 10 mm (or twice the slice thickness if slices are not 5 mm thick) in the longest diameter (LD) from a non-irradiated area:
    • Lymph nodes lesion ≥ 15 mm in the shortest diameter from a non-irradiated area;
    • If target lesion(s) are located within previously irradiated area patients can be enrolled if:
      • target lesions have not been irradiated within the last 3 months;
      • there has been demonstrated progression in the “in field” target lesion and after sponsor acceptance,
  • In the dose escalation part, patients with ovarian cancer can be included based on CA 125 positivity according to the Gynecologic Cancer Intergroup Guideline1, 2; only if they have a pretreatment sample that is at least twice the upper limit of the reference range and within 2 weeks before starting the treatment.
    • Note: Patients are not evaluable by CA 125 if they have received mouse antibodies (unless the assay used has been shown not to be influenced by human anti-mouse antibody) or if there has been medical and/or surgical  interference with their peritoneum or pleura during the previous 28 days (e.g., paracentesis).
• In the dose escalation part all patients must provide a tumor tissue sample (Formalin Fixed Paraffin Embedded (FFPE) blocks / slides) from archival tissue or fresh biopsy collected before Cycle 1, Visit 1, preferably derived from advanced disease stage.
• In the expansion part all patients must provide a mandatory fresh biopsy (FFPE tissue blocks/slides) at screening (aspirates are not acceptable) which contains tumor tissue and is taken after failure/stop of last prior treatment. Documentation of the fresh FFPE biopsy shipment must be submitted to the Sponsor as a part of eligibility package prior to administration of first dose of enapotamab vedotin. In case it is not feasible to meet the required criteria for fresh tumor biopsy, the sponsor medical officer’s approval of enrollment is needed. Furthermore, the latest available archival tumor tissue sample must be collected if available.
• Age ≥ 18 years.
• Have an acceptable renal function defined as:
  • Glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m² – e.g., according to the abbreviated Modification of Diet in Renal Disease (MDRD) equation:
  • GFR = 186 × (SCr-1.154) × (age-0.203) (where SCr, the serum creatinine level, is expressed in mg/dL; multiply it by 0.742 if the patient is female; multiply it by 1.212, if the patient is African-American);
  • Not being on dialysis.
• Have an acceptable liver function defined as:
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the ULN; if liver tumor/ metastases are present, then ≤ 5 x ULN is allowed;
  • Bilirubin ≤ 1.5 x ULN, except in patients diagnosed with Gilbert’s syndrome, direct bilirubin ≤ 2 x ULN.
• Have an acceptable hematological status defined as:
  • Hemoglobin ≥ 5.6 mmol/L (~ 9 g/dL);
  • Absolute neutrophil count (ANC) ≥ 1500/μL (1.5 x 10^9/L);
  • Platelet count ≥ 100 x10^9/L.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Life expectancy of at least 3 months.
• Patients, both females and males, of childbearing/reproductive potential must agree to use adequate contraception while included in the trial and for 6 months after the last infusion of enapotamab vedotin.
• Patients must provide signed ICF.

Exclusion Criteria:

Hematological

• 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 thromboembolicprophylaxis.

Cardiovascular

• Have clinically significant cardiac disease, including:
  • Onset of unstable angina within 6 months of signing the ICF.
  • Acute myocardial infarction within 6 months of the signing the 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.

Immunological

• 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 a history of non-infectious pneumonitis related to prior systemic treatment and that required treatment with steroids within the last 6 months prior to enrolment.
  • If an event of pneumonitis is considered fully resolved more than 6 months prior trial start, i.e., patient has no radiologic evidence of pneumonitis, is asymptomatic and does not require any steroid treatment, patient can be enrolled.

Excluded medications or treatment regimens

• 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.

Surgery/procedures

• Major surgery within 4 weeks before first enapotamab vedotin administration.

Central nervous system

• Any history of intracerebral arteriovenous malformation, cerebral aneurysm, brain metastases or stroke.
  • Transient ischemic attack ≥ 6 months prior to screening is allowed.
  • Patients with known or suspected central nervous system metastases must undergo a Computed Tomography (CT) scan or Magnetic Resonance Imaging (MRI) of the brain and/or spinal cord for documentation of baseline disease status. Spinal cord metastasis is acceptable. However, patients  with known spinal cord compression that is symptomatic or patients who have not undergone definitive treatment for the spinal cord compression and subsequently do not have evidence of clinically stable disease (SD) for at least 28 days should be excluded.
    • In the expansion cohorts the enrolment of patients with stable brain metastases, i.e., being asymptomatic for the last 14 days prior to treatment initiation, is allowed;
    • Symptomatic uncontrolled brain or leptomeningeal metastases. (To be considered “controlled”, central nervous system [CNS] disease must have undergone treatment [e.g., radiation or chemotherapy] at least 2 weeks prior to first enapotamab vedotin administration. The patient must not have any new or progressive signs or symptoms related to the CNS disease and must be taking ≤ 10 mg of prednisone or equivalent per day or no steroids). Patients who have untreated brain metastases and who are not symptomatic may enroll if the investigator feels that treatment of these metastases is not indicated. Patients with spinal cord compression may be considered for enrolment if they have received definitive treatment for this and evidence of clinically stable disease (SD) for at least 28 days.

Prior therapy

• Any anticancer therapy including; small molecules, immunotherapy, chemotherapy monoclonal antibodies or any other experimental drug within 5 half-lives but maximum 4 weeks before first infusion. Accepted exceptions are bisphosphonates, denosumab and gonadotropin-releasing hormone agonist or antagonist, which can be continued throughout the trial.
  • Toxic effects of prior anti-cancer therapy considered as chronic, such as chemotherapy-induced fatigue, alopecia, or anorexia of ≤ Grade 2, where no more resolution is expected, does not prevent the patient from participation in the trial.
• Any prior therapy with a conjugated or unconjugated auristatin derivative/vinca-binding site targeting payload. Previous treatment with vinca alkaloids is allowed.
• Radiotherapy within 14 days prior to first enapotamab vedotin administration. Palliative radiotherapy will be allowed.

Other cancer/metastases

• 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.

Other

• 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.
• Presence of ≥ Grade 2 peripheral neuropathy.
• Clinically significant active viral, bacterial or fungal infection requiring:
  • l.v. treatment with anti-infective therapy that has been administered less than two weeks prior to first dose; or
  • Oral treatment with anti-infective therapy that has been administered less than one week prior to first dose;
  • Prophylactic anti-infective therapy, which is given without clinical symptomatic is allowed (e.g., antibiotic prophylaxis prior to dental extraction, etc.).
• Known human immunodeficiency virus seropositivity.
• Known history / positive serology for hepatitis B (unless immune due to vaccination or resolved natural infection or unless passive immunization due to immunoglobulin therapy):
  • Positive test for antibodies to hepatitis B core antigens (anti-HBc); and
  • Negative test for antibodies to hepatitis B surface antigens (anti-HBs).
• Known positive serology for hepatitis C (unless due to immunoglobulin therapy or completely resolved natural infection).
• 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.

Specifically for NSCLC

• Pulmonary hemorrhage or hemoptysis > 2.5 ml blood within 6 weeks unless cause has been addressed and is medically resolved.