E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced Solid Tumors and Hematological Malignancies |
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E.1.1.1 | Medical condition in easily understood language |
solid tumours or blood cancer |
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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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065143 |
E.1.2 | Term | Malignant solid tumour |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066481 |
E.1.2 | Term | Hematological malignancy |
E.1.2 | System Organ Class | 100000004864 |
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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 |
Dose-finding: -To determine the adult equivalent exposure/MTD/recommended Phase II pediatric dose of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy.
-To determine the safety profile of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy
Dose-expansion: To determine the preliminary antitumor activity of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy at the recommended dose, using cohortspecific response criteria (eg, Cheson criteria and RECIST 1.1). |
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E.2.2 | Secondary objectives of the trial |
Dose-finding and dose-expansion:
-To describe the PK of durvalumab and tremelimumab in combination and durvalumab as monotherapy following combination therapy, in children and young adults with solid tumors, or hematological malignancies
-To determine the immunogenicity of durvalumab and tremelimumab in combination and durvalumab as monotherapy following combination therapy, in children and young adults with solid tumors
-To determine the immunogenicity of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy, in children and young adults with hematological malignancies
-To measure effects on immune checkpoint inhibition in response to routine immunizations (dose-expansion phase only).
-To evaluate immune activation and counts of NK-, B- and T-cells |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Patients must have pathologically confirmed relapsed or refractory advanced solid tumour malignancy or haematological malignancies including lymphoma and acute leukaemia. Any number of prior treatment regimens allowed. A select group of first-line patients may be eligible for screening and enrolment. These patients will be enrolled based on investigator assessment as patients for whom no curative standard of care treatment options exist or such therapies are not tolerable.
• If available, patients must provide a diagnostic tumor sample taken ˂3 years prior to screening for evaluation of PD-L1 status.
• Lansky play performance scale ≥50 for patients ≥1 and <16 years of age and Karnofsky performance status score ≥50 for patients ≥16 years of age (patients <1 year of age are exempt from this criterion)
• Patients must have measurable/evaluable disease as defined by methods used in common clinical practice.
• No prior exposure to immune checkpoint inhibitors or genetically engineered cellular therapies including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2 antibodies and antibodies of CAR-T or other cell therapies, excluding therapeutic anticancer vaccines. Exposure to other investigational agents may be permitted after discussion with the Sponsor or designee. |
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E.4 | Principal exclusion criteria |
• History of allogeneic organ transplantation (exceptions may be allowed for HL, NHL, ALL and AML, after discussion with Sponsor or designee). Patients who have previously received an autologous bone marrow transplant may be eligible
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, diverticulitis, celiac disease or other serious GI chronic conditions associated with diarrhea, systemic lupus erythematosus, Wegener syndrome; myasthenia gravis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc) autoimmune myocarditis, and autoimmune pneumonitis. The following are exceptions to this criterion: − Patients with vitiligo or alopecia − Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement − Psoriasis that does not require systemic therapy − Patients with celiac disease controlled by diet alone.
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, cardiac arrhythmia, ILD, or psychiatric illness or social situations that would limit compliance with study requirements, substantially increase risk of incurring AEs from IP, or compromise the ability of the patient to give written informed consent.
• History of primary immunodeficiency.
• Active infection including tuberculosis, hepatitis B, hepatitis C, or HIV. Patients with a past or resolved HBV infection are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).
• Any unresolved toxicity NCI CTCAE version 5.0 Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, lymphopenia and the laboratory values defined in the inclusion criteria − Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis and may be included after consultation with the Study Physician. − Patients with toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab (eg, hearing loss, gastrostomy tube) may be included after consultation with the Study Physician.
• Patients with clinically active brain metastases (known or suspected) or spinal cord compression, and choloromas are excluded, unless these conditions have been previously treated and are considered stable.
• History of leptomeningeal carcinomatosis, or involvement of any other anatomic area that, in the opinion of the Investigator, may cause significant symptoms if an inflammatory reaction occurs. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Dose-finding: 1. Based on PK parameters (including Cmax, Cmin, AUC, and others), identify the adult equivalent exposure/MTD of durvalumab monotherapy and durvalumab in combination with tremelimumab among children and young adults from birth to <18 years of age with advanced solid tumors and non-Hodgkin lymphoma, using a q4w dosing schedule. 2. Identify the safety and tolerability of durvalumab monotherapy and durvalumab in combination with tremelimumab at the adult equivalent exposure/MTD among children and young adults from birth to <18 years of age with advanced solid tumors and non-Hodgkin lymphoma, using a q4w dosing schedule. Endpoints include AEs, vital signs, physical examinations, ECGs, and laboratory evaluations.
Dose-expansion: 3. Objective response rate as determined by the Investigator assessed RECIST 1.1 or alternative pre-specified tumor-specific response rates for different scoring systems. -Assessment of antitumor activity will be specific to tumor cohort, eg, Investigator assessed RECIST 1.1 and Cheson criteria (other malignancies will be analyzed based on the best response assessed by the Investigator). 4. Additional efficacy endpoints that will be collected include DoR, BoR, DCR, PFS, APF12, and APF18 based on RECIST 1.1, Cheson criteria, Wayne criteria, or INRC assessed by the Investigator, and OS, OS12, and OS24 as appropriate to each individual cohort. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. From first dose to cycle 12 on dosing days
2. From baseline to 90 days post-treatment discontinuation (for AEs)
3. From baseline to progression
4. From baseline to death/data cut-off for analysis (survival) |
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E.5.2 | Secondary end point(s) |
5. Individual durvalumab and tremelimumab concentrations in serum, and PK parameters including Cmax, Cmin, AUC.
6. Number and percentage of patients who develop detectable ADAs.
7. Individual antibody titer measurements before and after planned routine immunization during treatment and Cycle 4 or follow-up, whichever is earlier.
8. Flow cytometry for CD4, CD8, B and NK cells, including T-cell activation with Ki67 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
5. From first dose to cycle 12 on dosing days
6 & 7. Pre- first dose and pre-dose cycle 6 (durvalumab) and cycle 4 (tremelimumab)
8. From first dose to cycle 2 |
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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 | 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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Dose-finding & Dose-expansion |
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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 | 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.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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 |
United States |
France |
Germany |
Italy |
Netherlands |
Spain |
United Kingdom |
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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
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The end of the study is defined as 'the last visit of the last patient undergoing the study'. |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |