| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Epithelial Ovarian Cancer, Primary Peritoneal Cancer or Fallopian Tube Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Cancer of ovary and related organs |
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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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061269 |
| E.1.2 | Term | Malignant peritoneal neoplasm |
| 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 | 10061328 |
| E.1.2 | Term | Ovarian epithelial 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.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To compare the progression free survival (PFS) of patients randomized to IMGN853 versus selected standard of care chemotherapy (IC), as assessed by the blinded independent review committee (BIRC), in the intent to treat (ITT) population (defined as all randomized patients) and in the high FRα subgroup (≥ 75% of tumor staining at ≥2+ intensity) |
|
| E.2.2 | Secondary objectives of the trial |
Key Secondary Objectives:
• To compare the objective response rate (ORR) of patients randomized to IMGN853 versus selected standard of care chemotherapy (IC)
- Primary analysis of ORR will be based on BIRC assessments.
ORR based on investigator’s assessment will be analyzed as sensitivity analysis.
• To compare the primary PRO endpoint using QLQ-OV28 assessments from patients randomized to IMGN853 versus selected standard of care chemotherapy (IC)
• To compare the overall survival (OS) of patients randomized to IMGN853 versus selected standard of care chemotherapy (IC)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients must have one of the following pathologically documented, definitively diagnosed tumor types:
a. Advanced EOC
b. Primary peritoneal cancer
c. Fallopian tube cancer
2. Patients must have platinum-resistant ovarian cancer, defined as progression within 6 months from completion of a minimum of four cycles of platinum-containing therapy. This should be calculated from the date of the last administered dose of platinum therapy to the date of the radiographic imaging showing progression.
3. Patients must have at least one lesion that meets the definition of measurable disease by RECIST v1.1.
4. Patients must have received at least one but no more than three prior systemic lines of anti-cancer therapy and for whom single agent chemotherapy is appropriate as the next line of treatment.
a. Adjuvant±Neoadjuvant will be considered as one line of therapy
b. Maintenance therapy (example: bevacizumab, PARP inhibitors) will be considered as part of the preceding line of therapy (i.e., not counted independently)
5. Patients must be willing to provide an archival tumor tissue, or fresh biopsy collected using a non-significant risk procedure. Patients who do not have archival tissue and for whom the only sites of disease would require biopsy procedure considered to be of significant risk must not be enrolled in the study. These significant risk procedures include (but are not limited to) biopsies of the brain, lung/mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, stomach or bowel.
6. Patients must have confirmation of FRα positivity by Ventana IHC test (≥ 50% of tumor staining at ≥2+ intensity) in archival or fresh biopsy tumor sample. If the archival tumor tissue does not meet FRα criteria, a fresh biopsy tumor sample may be submitted and if positive, it may be used to meet this criterion.
7. Female patients ≥ 18 years of age
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
9. Time from prior therapy:
a. Systemic anti-neoplastic therapy: five half-lives or four weeks, whichever is shorter
b. Focal radiation completed at least two weeks, prior to starting study drug
10. Patients must have stabilized or recovered (Grade 1 or baseline) from all therapy-related toxicities.
11. Major surgery (not including placement of vascular access device or tumor biopsies) must be completed four weeks prior to Day 1. Patients must have recovered or stabilized from the side effects prior to study treatment
12. Patients must have adequate hematologic, liver and kidney function as defined by the following parameters:
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (1,500/μL)
b.Platelet count ≥ 100 x 109/L (100,000/μL); no transfusion within previous 10 days
c. Hemoglobin ≥ 9.0 g/dL
d. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or 24-hour creatinine clearance of ≥ 60 mL/minute
e. AST ≤ 3.0 x ULN; ALT ≤ 3.0 x ULN
f. Serum bilirubin ≤ 1.5 x ULN (Patients with documented diagnosis of Gilbert syndrome are eligible if total bilirubin < 3.0 x ULN)
g. Serum albumin ≥ 2 g/dL
13. Patients must be willing and able to sign the informed consent form, and to adhere to the study visit schedule and other protocol requirements.
14. Women of childbearing potential (WCBP) are defined as a sexually mature woman who has not undergone surgical sterilization or who has not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months). WCBP must agree to use effective contraceptive methods (examples include oral, parenteral, or implantable hormonal contraceptive, intra-uterine device, or vasectomy) while on study treatment and for at least twelve weeks after the last dose of IMGN853 and for at least six months after the last dose of paclitaxel, PLD or topotecan (Refer to Section 5.9.7).
15. WCBP must have a negative pregnancy test prior to the first dose of study treatment.
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| E.4 | Principal exclusion criteria |
1. Male patients
2. Patients with clear cell, mucinous histology, mixed histology with mucinous component, sarcoma, sarcomatous component, or low grade ovarian cancer
3. Patients with primary platinum-refractory disease as defined by those who progressed during or within four weeks of completion of first platinum-based chemotherapy).
4. Patients who have received prior wide-field radiotherapy affecting at least 20% of the bone marrow
5. Patients with uncontrolled bleeding disorders or inadequate coagulation parameters:
a. Activated partial thromboplastin time (aPTT) )>1.5 x ULN, unless related to lupus anticoagulant. Patients receiving unfractionated heparin must have aPTT between 1.5 and 2.5 x ULN or within a range determined by their physician.
b. International normalized ratio (INR)>1.5. Patients receiving warfarin must have an INR between 2.0 and 3.0 or within a range determined by their physician
6. Patients with > Grade 1 peripheral neuropathy
7. Active or chronic corneal disorders such as Sjogren’s syndrome, Fuchs corneal dystrophy (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, active diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, and /or monocular vision.
8. Serious concurrent illness or clinically-relevant active infection, including, but not limited to the following:
a. Known active hepatitis B or C whether or not on active antiviral therapy
b. Known Human Immunodeficiency Virus (HIV) infection
c. Varicella-zoster virus (shingles)
d. Cytomegalovirus infection
e. Any other known concurrent infectious disease, requiring IV antibiotics within 2 weeks of starting study treatment
9. Clinically-significant cardiac disease including any one of the following:
a. Recent myocardial infarction (≤ 6 months prior to day 1)
b. Unstable angina pectoris
c. Uncontrolled congestive heart failure (New York Heart Association > class II), uncontrolled hypertension (≥ CTCAE v4.03 Grade 3)
d. Uncontrolled hypertension (≥ CTCAE v4.03 Grade 3)
e. If the choice of chemotherapy agent is PLD for patients randomized to the IC chemotherapy arm, LVEF (measured by Echocardiography (ECHO) or Multigated Acquisition (MUGA) scan) that is below the institutional limit of normal
f. Clinically-significant vascular disease (e.g. aortic aneurysm, or dissecting aneurysm)
g. Severe aortic stenosis
h. Clinically significant peripheral vascular disease, or ≥ Grade 3 cardiac toxicity following prior chemotherapy
I. Corrected QT (QTc) >470 msec using on-screening ECG
10. History of neurological condition, or concurrent neurological condition that would confound assessment of treatment-emergent neuropathy
11. History of multiple sclerosis or other demyelinating disease and/or Eaton-Lambert syndrome (para-neoplastic syndrome)
12. History of hemorrhagic or ischemic stroke within the last 6 months
13. History of cirrhotic liver disease
14. Previous clinical diagnosis of non-infectious interstitial lung disease, including non-infectious pneumonitis
15. Required use of folate –containing supplements (e.g. folate deficiency)
16. Prior hypersensitivity to monoclonal antibodies
17. Women who are pregnant or lactating
18. Patients with known hypersensitivity to any of the SOC chemotherapy agents included in the study (paclitaxel, PLD, or topotecan) are excluded from receiving that particular medicinal product, but can receive one of the other chemotherapy agents included in the study.
19. Untreated CNS disease or symptomatic CNS metastasis
20. Prior treatment with IMGN853 or prior treatment on the study
21. History of other clinically active malignancy within 3 years of enrollment, except for tumors with a negligible risk for metastasis or death, such as adequately controlled basal-cell carcinoma or squamouscell carcinoma of the skin or carcinoma in situ of the cervix or breast
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Progression-free survival (PFS): the time from the date of randomization until the time of death or PD, as assessed by the BIRC
-In all patients randomized to the study
-In patients with high FRα level (≥ 75% of tumor staining at
≥2+ intensity) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Radiologic tumor assessments: Every 6 weeks (± 1 week) for first 36 weeks then every 12 weeks (± 1 week)
|
|
| E.5.2 | Secondary end point(s) |
Key Secondary Endpoints
• Objective response rate (ORR) per RECIST 1.1 criteria as assessed by BIRC
• Primary endpoint for Quality of life using the QLQ-OV28 questionnaire as described in Section 11.7. of the protocol
• Overall survival (OS): the time from the date of randomization until the date of death
Other Secondary Endpoints
• Treatment-emergent adverse events and laboratory test results, physical examination, ECGs or vital signs.
• Gynecologic Cancer Intergroup (GCIG) CA-125 criteria clinical response rate
• Time to event endpoints
− PFS as assessed by investigator
− Duration of response (DOR): the time from first objective response (CR/PR) to the time of PD among those who have achieved a PR or CR
• PK parameters of IMGN853
• Immunogenicity of IMGN853: ADA
• All other endpoints for Quality of Life as assessed using the EORTC QLQ-C30, EORTC QLQ-OV28, EQ-5D-5L and eight-item FOSI questionnaires |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Key secondary endpoint:
Radiologic tumor assessments: Every 6 weeks ± 1 week) for first 36 weeks then every 12 weeks (± 1 week)
Other secondary endpoint:
AE and SAE assessments: every study visit
lab test results: every study visit
physical examination - every study visit
CA-125 - At day 1 of each cycle and at every 6 weeks (± 1 week) for first 36 weeks then every 12 weeks (± 1 week)
Time to event endpoints - PFS as assessed by investigator
Radiologic tumor assessments: Every 6 weeks ± 1 week) for first 36 weeks then every 12 weeks (± 1 week)
DOR - radiologic tumor assessments: Every 6 weeks ± 1 week) for first 36 weeks then every 12 weeks (± 1 week)
QOL questionnaires - screening, Day 1, Every 8 weeks (± 1 week) until disease progression as assessed by BIRC, EOT
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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 | Yes |
| 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 | Yes |
| 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) | 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 | 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) | 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 | 70 |
| 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 |
| Austria |
| Belgium |
| Bosnia and Herzegovina |
| Bulgaria |
| Canada |
| Czech Republic |
| France |
| Hungary |
| Ireland |
| Italy |
| Poland |
| Russian Federation |
| Serbia |
| Spain |
| Switzerland |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| End of study is defined as the date when the last patient on study has completed the one year survival follow-up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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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