| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer (hereafter collectively referred to as platinum-resistant ovarian cancer and abbreviated as PROC) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016180 |
| E.1.2 | Term | Fallopian tube cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10080244 |
| E.1.2 | Term | Peritoneal cancer index |
| E.1.2 | System Organ Class | 10022891 - Investigations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
(Safety run-in) Evaluate safety and tolerability of a dose-dense regimen of tisotumab vedotin
(Parts A and B) Evaluate antitumor activity of tisotumab vedotin |
|
| E.2.2 | Secondary objectives of the trial |
Evaluate the safety and tolerability of tisotumab vedotin
Evaluate preliminary antitumor activity of tisotumab vedotin
Evaluate antitumor activity of tisotumab vedotin
Evaluate durability of response in patients who respond to tisotumab vedotin
Evaluate stability and control of disease
Evaluate the timing of responses
Evaluate PFS of patients treated with tisotumab vedotin
Evaluate survival of patients treated with tisotumab vedotin
Assess pharmacokinetics of tisotumab vedotin
Assess immunogenicity of tisotumab vedotin
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologic documentation of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer (excluding carcinosarcoma, mucinous, and low grade serous histologies), hereafter referred to as “ovarian cancer”.
2. Safety run-in patients only: Platinum-resistant ovarian cancer (PROC), which is defined as having progressed or relapsed within 6 months after previous platinum-containing chemotherapy and for which single agent chemotherapy is appropriate. Progression or relapse must be documented radiographically using RECIST v1.1 criteria. The patient may have received more than 1 prior systemic treatment regimen in the PROC setting.
3. Part A and Part B patients only: PROC; with the following prior treatment requirements:
●The patient must have received 1 to 3 prior anticancer lines of therapy overall, including at least 1 line of therapy containing bevacizumab or a biosimilar to bevacizumab.
●Adjuvant ± neoadjuvant are considered 1 line of therapy.
●Patients may have received a PARP inhibitor or an immuno-oncology (IO) agent; any of these regimens are to be considered a line of therapy for the purposes of this study if not used as maintenance therapy.
●Maintenance therapy (including bevacizumab, PARP inhibitors and IOs) will be considered part of the preceding line of therapy and not to be counted as a new line of therapy.
●Any chemotherapy regimen change due to toxicity in the absence of disease progression is considered as part of the same line of therapy.
●Hormonal therapy will be not be counted towards the lines of therapy.
4. Measurable disease according to RECIST v1.1 as assessed by the investigator, defined as:
a. A minimum of one non-nodal lesion ≥10 mm in the longest diameter from a non-irradiated area. If target lesion(s) are located within previously irradiated area only, the patient can be enrolled only if there has been demonstrated progression in the “in field” lesion and upon approval of the sponsor’s medical monitor.
OR
b. Lymph node lesion ≥15 mm in the shortest diameter from a non-irradiated area.
5. Age 18 years or older.
6. An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 (see Appendix E for conversion of performance status using Karnofsky and Lansky scales, if applicable).
7. The following baseline laboratory data:
● Absolute neutrophil count (ANC) ≥1500/μL assessed at least 2 weeks after growth factor support, if applicable.
● Platelet count ≥100 x 109/L assessed at least 2 weeks after transfusion with blood products.
● Hemoglobin ≥5.6 mmol/L (9.0 g/dL) assessed at least 2 weeks after transfusion with blood products.
● Serum bilirubin ≤1.5 x upper limit of normal (ULN) or direct bilirubin ≤2 x ULN in patients diagnosed with Gilbert’s syndrome.
● Estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) study equation as applicable
● Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN. (If liver tumor/metastases are present, then <5 x ULN is allowed).
8. Acceptable coagulation status:
● INR ≤1.2 without anticoagulation therapy.
● aPTT ≤1.25 ULN.
9. Life expectancy of at least 3 months.
10. Patients of childbearing potential as defined in Section 4.3, under the following conditions:
● Must have a negative serum or urine pregnancy test (minimum sensitivity 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 7 days prior to the first dose of tisotumab vedotin.
● Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 6 months after the final dose of study drug administration.
Must agree to complete abstinence or, if sexually active in a way that could lead to pregnancy, must consistently use 2 highly effective methods of birth control (as defined in Appendix F) starting at time of informed consent and continuing throughout the study and for at least 6 months after the final dose of study drug administration.
11.Able to provide fresh or archival tissue for biomarker analysis. Fresh tissue must be obtained from a newly obtained core or excisional biopsy of a tumor lesion. Archived specimens must have been collected within 2 years of first administration of tisotumab vedotin. Older specimens may be allowed upon approval of the sponsor's medical monitor.
12.The patient or the patient's legally authorized representative must provide written informed consent. |
|
| E.4 | Principal exclusion criteria |
1.Primary platinum-refractory disease, defined as disease progression within 3 months of completion of first line platinum-based therapy.
2. Patients with clinical symptoms or signs of gastrointestinal obstruction within the past 6 months or who currently require parenteral nutrition.
3.Hematological: Known past or current coagulation defects leading to an increased risk of bleeding; diffuse alveolar hemorrhage from vasculitis; known bleeding diathesis; ongoing major bleeding; trauma with increased risk of life-threatening bleeding or history of severe head trauma or intracranial surgery within 8 weeks of trial entry.
4. Cardiovascular: Clinically significant cardiac disease including uncontrolled hypertension (systolic BP >150 mmHg or diastolic BP >90 mmHg), unstable angina, acute myocardial infarction within 6 months prior to screening, serious cardiac arrhythmia requiring medication (not including asymptomatic atrial fibrillation with controlled ventricular rate); any medical history of congestive heart failure (Class II or higher as classified by the New York Heart Association, see Appendix H), or any medical history of decreased cardiac ejection fraction of <45%.
5. Ophthalmological: Active ocular surface disease at baseline. An ocular evaluation is to be confirmed by an ophthalmologist at screening. Patients with any prior episode of cicatricial conjunctivitis or Stevens Johnson syndrome (as evaluated by the investigator) are ineligible. Cataract is not considered active ocular surface disease for this study.
6.History of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival ≥90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, ductal carcinoma in situ, or stage I uterine cancer.
7.Inflammatory bowel disease including Crohn’s disease and ulcerative colitis
8.Ongoing, acute, or chronic inflammatory skin disease.
9.Uncontrolled tumor-related pain
10.Inflammatory lung disease, including moderate and severe asthma and chronic obstructive pulmonary disease, requiring chronic medical therapy
11.Grade 3 or higher pulmonary disease unrelated to underlying malignancy
12.Patients with significant peripheral vascular disease
13.Uncontrolled pleural or pericardial effusions |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Incidence of DLTs or other unacceptable toxicities
Investigator-determined confirmed ORR as measured by RECIST v1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety and tolerability will be assessed at every visit and via phone calls as needed between visits.
|
|
| E.5.2 | Secondary end point(s) |
| The confirmed and unconfirmed ORR according to RECIST v1.1, CA-125 response rate, combined RECIST/CA-125 overall response rate, and the DCR will be estimated and the 95% CIs will be calculated. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Radiographic tumor assessments
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Denmark |
| Ireland |
| Italy |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The date the patient met criteria for study discontinuation and the reason for study discontinuation will be recorded. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 12 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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