| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Second- or Third-Line Recurrent or Metastatic Cervical Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Second- or Third-Line Cervical Cancer |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008342 |
| E.1.2 | Term | Cervix carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| To demonstrate improvement in clinical efficacy of tisotumab vedotin compared to chemotherapy in subjects with second- or third-line (2L-3L) cervical cancer |
|
| E.2.2 | Secondary objectives of the trial |
• To further demonstrate improvement in clinical efficacy of tisotumab vedotin compared to chemotherapy in subjects with 2L-3L cervical cancer
• To demonstrate improvement in antitumor activity of tisotumab vedotin compared to chemotherapy in subjects with 2L-3L cervical cancer
• To characterize the antitumor response of tisotumab vedotin and chemotherapy in participants with 2L-3L cervical cancer
• To evaluate the safety and tolerability of tisotumab vedotin
• To assess health-related quality of life (HRQOL) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Age ≥18 years, or considered an adult by local regulations, at time of consent.
2.Must sign an informed consent form (ICF) indicating that they understand the purpose of and procedures required for the trial and are willing to participate in the trial prior to any other trial-related assessments or procedures.
3.Has recurrent or metastatic cervical cancer with squamous cell, adenocarcinoma, or adenosquamous histology, and:
a.Has experienced disease progression during or after treatment with standard of care systemic therapy defined as either:
- paclitaxel+cisplatin+bevacizumab, or + anti-PD-(L) 1 agent, or
- paclitaxel+carboplatin+bevacizumab, or + anti-PD-(L) 1 agent, or
- paclitaxel+topotecan/nogitecan+bevacizumab + anti-PD-(L) 1 agent
b.Has received 1 or 2 prior systemic therapy regimens for recurrent and/or metastatic cervical cancer.
c.Is not a candidate for curative therapy, including but not limited to radiotherapy or exenterative surgery.
4. Measurable disease according to RECIST v1.1 as assessed by the investigator
5.Acceptable screening laboratory values including renal function, liver function and hematological status.
6.Has ECOG PS of 0 or 1 prior to randomization.
7. Has life expectancy of at least 3 months.
8.Has a negative serum pregnancy test for female subjects of reproductive potential. Subjects that are postmenopausal or permanently sterilized can be considered as not having reproductive potential.
9.Subjects of reproductive potential must agree to use adequate contraception during and for 6 months after the last trial treatment administration.
10. Must agree not to breastfeed or donate ova, starting at the time of informed consent and continuing through 6 months after receiving the last dose of study drug administration.
11.Where required by local health authorities, has negative serology for hepatitis B surface antigen (HBsAg)/HBV DNA, or hepatitis C antibody (HCVAb) or RNA. Active hepatitis C is defined by a known positive HCVAb result and known quantitative HCV RNA results greater than the lower limits of detection of the assay.
12. Must be willing and able to adhere to the prohibitions and restrictions specified in this protocol. |
|
| E.4 | Principal exclusion criteria |
1. Primary neuroendocrine, lymphoid, sarcomatoid, or other histologies not mentioned in inclusion criterion 3
2. Clinically significant bleeding issues or risks
3. Clinically significant cardiac disease
4. History of intracerebral arteriovenous malformation, cerebral aneurysm, or stroke
5. Ocular surface disease Common Terminology Criteria for Adverse
Events (CTCAE) grade 2 or above, any prior episode of cicatricial
conjunctivitis, or any prior episode of Stevens-Johnson syndrome.
6.Other cancer: known past or current malignancy other than inclusion diagnosis. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5year OS ≥90%) such as non-invasive basal cell or squamous cell skin carcinoma; non-invasive, superficial bladder cancer, any ductal carcinoma in situ.
7. Brain metastases are allowed if the following criteria are met: definitive therapy (eg, surgery or stereotactic brain radiotherapy) has been completed >8 weeks before the first dose of study treatment; no evidence of clinical or radiologic progression of the brain metastases; participant has completed perioperative corticosteroid therapy or steroid taper.
8.Surgery/procedures: major surgery within 4 weeks or minor surgery within 7 days prior to the first trial treatment administration. Subjects must have recovered adequately from the toxicity or complications from the intervention prior to starting trial treatment. Subjects who have planned major surgery during the treatment period must be excluded from the trial.
9.Peripheral neuropathy ≥grade 2.
10.Prior anti-cancer therapy:
a.Any prior treatment with MMAE-derived drugs.
b.Radiotherapy within 21 days prior to the first administration of trial
treatment. Subjects must have recovered from all clinically significant
radiation-related toxicities. At least 42 days must have elapsed from the last administration of chemo radiotherapy.
c. Is currently participating in or has participated in a trial of an
investigational agent or device and received active treatment within 28days prior to the first dose of trial treatment.
11. Other:
a. Ongoing significant, uncontrolled medical condition.
b. Clinically significant active viral, bacterial, or fungal infection requiring IV or oral treatment with antimicrobial therapy ending <7 days prior to first study treatment administration.
c. Clinically relevant bilateral hydronephrosis which cannot be alleviated by ureteral stents or percutaneous drainage.
d. Participants with clinical symptoms or signs of gastrointestinal obstruction and who require parenteral hydration or nutrition at the time of the first dose of study treatment.
12. Has known seropositivity of human immunodeficiency virus (HIV); known medical history of hepatitis B or C infection. Note: No testing for HIV, hepatitis B, or hepatitis C is required, unless mandated by local health authorities. Exceptions include latent or controlled HIV infection.
13. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (dose exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of tisotumab vedotin.
14. Is pregnant or intends to conceive children within 6 months of ending study treatment.
15. Is breast feeding and cannot discontinue breast feeding for the duration of the study and ≥6 months after the last study treatment administration.
16. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise well-being) or that could prevent, limit, or confound the protocol-specified assessments.
17. Known allergies, hypersensitivity, or intolerance to study treatment or its excipients.
18. Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| interim analysis (IA) and final analysis (FA) |
|
| E.5.2 | Secondary end point(s) |
•Progression-free survival (PFS) based on Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 as assessed by the investigator
•Confirmed overall response rate (ORR) based on RECIST v1.1 as assessed by the investigator
• Time-to-response (TTR) as assessed by the investigator
• DOR as assessed by the investigator
•Incidence of adverse events (AEs)
•EQ-5D-3L index
•EQ-5D visual analog scale (VAS)
•EORTC-QLQ-C30
•EORTC-QLQ-CX24 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| interim analysis (IA) and final analysis (FA) |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 68 |
| 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 |
| Argentina |
| Brazil |
| Canada |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Peru |
| Singapore |
| Taiwan |
| United States |
| Austria |
| Finland |
| France |
| Poland |
| Sweden |
| Netherlands |
| Spain |
| Czechia |
| Germany |
| Italy |
| Belgium |
| Denmark |
| Hungary |
| Ireland |
| Norway |
| Russian Federation |
| Slovakia |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 trial is considered completed when the last survival follow-up visit is completed or 5 years after randomization of the last subject participating in the trial, whichever occurs first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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