E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 10028980 |
E.1.2 | Term | Neoplasm |
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 |
-Phase1: To characterize the safety and tolerability of isatuximab in combination with atezolizumab in participants with unresectable hepatocellular carcinoma (HCC), platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN), platinumresistant/ refractory epithelial ovarian cancer (EOC), or recurrent glioblastoma multiforme (GBM), and to determine the recommended Phase 2 dose (RP2D).
- Phase2: To assess response rate (RR) of isatuximab in combination with atezolizumab in participants with HCC or SCCHN or EOC.
- Phase2: To assess the progression free survival rate at 6 months (PFS-6) of isatuximab in combination with atezolizumab, or as a single agent in participants with GBM. |
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E.2.2 | Secondary objectives of the trial |
-To evaluate the safety profile of isatuximab monotherapy (GBM only), or in combination with atezolizumab in Phase 2.
-To evaluate the immunogenicity of isatuximab and atezolizumab
-To characterize the pharmacokinetic (PK) profile of isatuximab single agent (GBM only) and atezolizumab in combination with isatuximab.
-To assess the overall efficacy of isatuximab in combination with atezolizumab, or single agent (GBM only). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Patients must have a known diagnosis of either unresectable
hepatocellular carcinoma (HCC), platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN), platinum-resistant/refractory epithelial ovarian cancer (EOC) with evidence of measurable disease
or recurrent glioblastoma multiforme (GBM).
- ≥18 years of age.
-For patients with HCC: Documentation of progressive disease (PD) during or after treatment with either sorafenib or lenvatinib, or intolerance to the therapy.
-For patients with SCCHN: Received and failed up to 2 lines of prior systemic anti-cancer therapy with documentation of tumor recurrence or PD within 6 months of last platinum-based therapy in primary, recurrent, or metastatic setting.
-For patients with EOC: Received up to 3 lines of prior platinum- containing therapy when the
disease was platinum-sensitive, and the patients should not have received any systemic therapy for
platinum-resistant/refractory disease. specific to France only:
Documentation of PD on or after 1 line
of anti-cancer therapy for platinum resistant/refractory disease (unless patients are ineligible or
intolerant to standard of care for platinum-resistant/refractory disease).
-For patients with GBM: Documentation of PD or first recurrence during or after temozolomide maintenance therapy for newly diagnosed GBM treated with 1st line radiotherapy plus concurrent temozolomide. |
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E.4 | Principal exclusion criteria |
- Prior exposure to agent that blocks CD38 or participation in clinical studies with isatuximab
- For patients with HCC, SCCHN, EOC or GBM prior exposure to any agent (approved or investigational) that blocks the PD-1/PD-L1 pathway.
- Evidence of other immune related disease /conditions.
- History of non-infectious pneumonitis requiring steroids or current pneumonitis; history of the thoracic radiation.
- Has received a live-virus vaccination within 28 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
- Prior solid organ or bone marrow transplantation.
- Eastern Cooperative Oncology Group performance status (PS) ≥2 for patients with HCC, SCCHN or EOC or Karnofsky performance score ≤ 70 for patients with GBM
- Poor bone marrow reserve.
- Poor organ function. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1) Dose Limiting Toxicities (DLTs): DLTs as observed during DLTobservation period
2) Adverse events (AEs): Number of patients with AEs based on standard and systematic assessment including changes in laboratory tests and vital signs, according to the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) version 4.03 Grade scaling
3) Maximum tolerated dose (MTD): MTD determined during Phase 1
4) Recommended Phase 2 dose (RP2D): Dose selected for the Phase 2 portion
5) Response Rate: In patients with unresectable hepatocellular carcinoma (HCC), platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN), platinumresistant/refractory epithelial ovarian cancer assessed by using RECIST 1.1
6) Progression free survival: In patients with glioblastoma multiforme (GBM) assessed by using Response Assessment for Neuro-Oncology (RANO) criteria at 6 months |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1), 3) and 4) Up to 3 weeks after first study treatment administration
2) Up to 90 days after last study treatment administration (Up to approximately 27 months after first study treatment administration)
5) Up to 6 months after last patient's first treatment in a given cohort
6) Up to 6 months after last patient's first treatment |
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E.5.2 | Secondary end point(s) |
1) Immunogenicity: isatuximab: Levels of anti-drug antibody against isatuximab
2) Immunogenicity: atezolizumab: Levels of anti-drug antibody against atezolizumab
3) Tumor burden change: The best percent-change from baseline in a sum of the diameters (longest for non-nodal lesion, short axis for nodal lesions) for all target lesions in participants with HCC, SCCHN and EOC, and in a sum of products of diameters for all target lesions in participants with GBM.
4) Disease control rate: The sum of complete responses (CR) + partial responses (PR) + stable disease (SD)
5) Duration of response: The time from the date of the first response (PR or CR in radiographic objective response) that is subsequently confirmed to the date of first confirmed disease progression or death, whichever occurs first.
6) Progress free survival: The time from the first study treatment administration to the date of first documentation of progressive disease (RECIST 1.1 for participants with HCC, SCCHN, EOC and RANO criteria for participants with GBM) or the date of death from any cause
7) Response Rate: In GBM assessed by RANO criteria
8) Pharmacokinetic (PK) parameters: Area under the curve (AUC0-T): AUC0-T is the area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (T; i.e., 7 days for isatuximab) after the first infusion
9) Assessment of PK parameter: Cmax: Cmax is maximum drug concentration observed
10) Assessment of PK parameter: tmax : Time to reach Cmax |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Up to 90 days following the last administration of study treatment (Up to approximately 27 months after first study treatment administration)
2) Up to 30 days following the last administration of study treatment (Up to approximately 25 months after first study treatment administration)
3) to 7) Up to 12 months after last patient's first treatment in a given cohort
8) to 10) From pre-isatuximab-dose on Cycle 1 Day 1 to 168 hours after start of isatuximab dose on Cycle 1 Day 1 (duration of assessment: 7 days; overall cycle duration: 21 days) |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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) | 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 | No |
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 | No |
E.8.2.4 | Number of treatment arms in the trial | 7 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 |
Canada |
Czech Republic |
France |
Greece |
Italy |
Netherlands |
Spain |
Taiwan |
United States |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | 24 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial days | 24 |