| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
This trial evaluates the efficacy and safety of Mirvetuximab soravtansine (IMGN853) plus Carboplatin chemotherapy in FRα high patients with recurrent ovarian cancer who are eligible for platinum-based chemotherapy.
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| E.1.1.1 | Medical condition in easily understood language |
| Safety and efficacy for carboplatin with Mirvetuximab soravtansine (IMGN853) compared to carboplatin combination chemotherapy |
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| 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 | 27.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057529 |
| E.1.2 | Term | Ovarian cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 | 10066697 |
| E.1.2 | Term | Ovarian cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 27.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016182 |
| E.1.2 | Term | Fallopian tube cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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) |
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| 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 |
| Progression free survival (PFS) defined as the time from randomization to progressive disease (PD) or death, whichever occurs earlier. PD is based on investigator assess-ment using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). |
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| E.2.2 | Secondary objectives of the trial |
• Overall survival (OS), defined as the time from randomization to death from any cause
• Objective Response Rate (ORR)
• Efficacy regarding PFS, OS and ORR depending on histologic subtype
• Time to serological progressive disease according to GCIG criteria
• Time to first subsequent treatment (TFST)
• Time to second subsequent treatment (TSST)
• Patient-reported outcomes: Quality of Life (EORTC C-30, OV28)
• Safety and tolerability of the used drugs evaluated by NCI CTCAE v5.0, records of dose reductions, delays, or interruptions
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Tumor tissue collection from current relapse (or if not feasible, tumor tissue obtained from previous surgeries) is mandated for the assessment of FRα expression status by PS2+ scoring applying the Ventana FOLR1 (FOLR1 2.1) CDx assay.
However, further exploratory work is planned on surplus tissue. An optional second FFPE tumor block will be collected and transferred to AGO biobank. This material may be used for additional exploratory work, to elucidate the mechanism of re-sponse/resistance, understand the mode of action of study treatment, and improve the understanding of the folate receptor pathway.
Exploratory biomarker data may be generated in real time during the study or retro-spectively and will have unknown clinical significance. AGO Study Group will not pro-vide exploratory biomarker results to patients, their family members, any insurance company, an employer, clinical study investigator, general physician or any other third party unless required to do so by law. The patient’s samples will not be used for any other purpose other than those dedicated to protocol related research.
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| E.3 | Principal inclusion criteria |
1. All patients must have a pathologically documented, definite diagnosis of epithelial cancer of the ovary, the fallopian tube or the peritoneum
2. Relapsed disease with a platinum-free interval >3 months
3. All histologic subtypes of ovarian carcinoma including carcinosarcoma (malignant mixed Mullerian tumors, MMMT)
4. Patients with wildtype BRCA1/2 mutation status or with a deleterious BRCA1/2 muta-tion in germline or somatic testing if they underwent PARP inhibitor therapy in previ-ous treatment line.
5. Patients must be willing to provide archival tumor tissue from current relapse or previ-ous surgeries/biopsies for central confirmation of FRα high status by PS2+ scoring:
all tumors must exhibit ≥75% of tumor cells with FRα membrane staining and ≥ 2+ in-tensity by immunohistochemistry (IHC) using the Ventana FOLR1 (FOLR1 2.1) CDx assay.
6. Patients must have measurable disease or evaluable disease in combination with GCIG CA-125 criteria.
7. Patients had one or more prior lines of chemotherapy. The last line of chemotherapy must have included platinum and has resulted in a partial or complete response.
8. Major surgery (not including placement of vascular access device, tumor punch/scrape biopsies or secondary wound closure) must be completed four weeks prior to Day 1.
9. Patients must have adequate hematological, liver, cardiac and kidney function:
a) Hemoglobin ≥ 10.0 g/dL.
b) Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
c) Platelet count ≥ 100 x 109/L.
d) Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).
e) Aspartate aminotransferase/Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT)) and Alanine aminotransferase/Serum Glutamic Pyruvate Transaminase (ALAT/SGPT)) ≤ 2.5 x ULN, unless liver metastases are pre-sent in which case they must be ≤ 5 x ULN.
f) Serum creatinine ≤ 1.5 x institutional ULN and glomerular filtration rate of at least 40 ml/minute according to Cockroft-Gault formula.
10. Patient is female and ≥18 years of age at the time of the first screening visit.
11. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
12. Patients must be willing and able to sign the informed consent form, and to adhere to the study visit schedule and other protocol requirements.
13. Women of childbearing potential (a woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently ster-ile. Permanent sterilization methods include hysterectomy, bi-lateral salpingectomy and bilateral oophorectomy) must have a negative serum pregnancy test within 3 days from day 1 of cycle 1 and agree to use a highly effective method of contraception while on study treatment and for at least 6 months after end of treatment. Such methods include:
a) Combined (estrogen and progestogen containing) hormonal contraception as-sociated with inhibition of ovulation:
• oral
• intravaginal
• transdermal
b) Progestogen-only hormonal contraception associated with inhibition of ovula-tion:
• oral
• injectable
• implantable
c) Intrauterine device (IUD)
d) Intrauterine hormone-releasing system (IUS)
e) Bilateral tubal occlusion
f) Vasectomized partner
g) Sexual abstinence
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| E.4 | Principal exclusion criteria |
1. Non-epithelial tumor origin of the ovary, the fallopian tube or the peritoneum (i.e. germ cell tumors)
2. Ovarian tumors of low malignant potential (e.g. borderline tumors).
3. Unknown BRCA status.
4. Patients who are planned to receive bevacizumab for the current relapse.
5. Other malignancy within the last 3 years (except cervix or breast in situ carcinoma, type I stage I endometrial cancer)
6. Patients who underwent surgery for the current relapse with macroscopic complete resection
7. Prior systemic anticancer therapy within 28 days before randomization
8. Prior treatment with folate receptor-targeting investigational agents is not allowed.
9. Patients with > Grade 1 peripheral neuropathy.
10. Serious concurrent illness or clinically-relevant active infection
11. Previous clinical diagnosis of non-infectious interstitial lung disease, including non-infectious pneumonitis.
12. Active or chronic corneal disorders such as Sjogren's syndrome, Fuchs corneal dys-trophy (requiring treatment), history of corneal transplantation, active herpetic keratitis, active ocular conditions requiring on-going treatment/monitoring such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, ac-tive diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, and /or monocular vision. Active or chronic corneal disorder
13. Required use of folate-containing supplements (e.g. folate deficiency)
14. Women of childbearing potential (WOCBP) not protected by highly effective contra-ceptive methods.
15. Pregnant and/or breast-feeding women.
16. Known hypersensitivity to one of the chemotherapy regimes and/or PARP Inhibitors and/or any of their excipients.
17. Patients with prior hypersensitivity to monoclonal antibodies.
18. Patients with potential risks according to contraindication, warnings or interactions of the used chemotherapeutic agents as stated in the SmPCs are not eligible for participation in this trial.
19. Patients with untreated or symptomatic central nervous system (CNS) metastases
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival (PFS) defined as the time from randomization to progressive disease (PD) or death, whichever occurs earlier. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The final analysis of the primary endpoint will be performed after observation of 95 PFS events in both arms.
The analysis of PFS will be performed in the ITT population. The analyses will be repeated in the PP population as sensitivity analyses |
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| E.5.2 | Secondary end point(s) |
• Overall survival (OS), defined as the time from randomization to death from any cause
• Objective Response Rate (ORR)
• Efficacy regarding PFS, OS and ORR depending on histologic subtype
• Time to serological progressive disease according to GCIG criteria
• Time to first subsequent treatment (TFST)
• Time to second subsequent treatment (TSST)
• Patient-reported outcomes: Quality of Life (EORTC C-30, OV28)
• Safety and tolerability of the used drugs evaluated by NCI CTCAE v5.0, records of dose reductions, delays, or interruptions |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints will be analyzed using appropriate statistical methodology. All details of secondary analyses will be specified in the Statistical Analysis Plan (SAP).
The safety analyses will be based on the as-treated population. All safety parameters will be summarized and also listed by patient. Summary tables will be presented for incidence rates (number of patients with at least one occurrence) of AEs, SAEs, AEs that led to premature withdrawal of trial treatment and interruptions/dose modifications, as well as summaries of severity (NCI CTCAE v5.0 grades) and causal relationship. |
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| 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 | No |
| 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| platinum-based chemotherapy |
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| 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 | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
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| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
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