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INFORM2 Study Uses Nivolumab and Entinostat in Children and Adolescents With High-risk Refractory Malignancies 第I相・フェーズ1, 第II相・フェーズ2 91 思春期
INFORM2 Exploratory Multinational Phase I/II Combination Study of Nivolumab and Entinostat in Children and Adolescents With Refractory High-risk Malignancies (INFORM2-NivEnt)
- Final4, 18-10-2023
- 2018-000127-14 (EudraCT番号)
- NCT-2017-0516 (その他の識別子) (Sponsor's No)
第II相・フェーズ2
high-risk CNS tumors
| 参加グループ/群 | 介入/治療法 |
|---|---|
実験的Nivolumab and Entinostat Combination Study of Nivolumab and Entinostat | Nivolumab and Entinostat Patients entering phase I will receive one week entinostat without nivolumab (priming phase) before receiving the combination treatment of nivolumab and entinostat. |
| 評価指標 | 指標の説明 | 時間枠 |
|---|---|---|
Phase I: Dose Limiting Toxicity (DLT) of the combination treatment. | A dose limiting toxicity (DLT) is defined as any AE according to the definitions and exceptions listed below that is related to the administration of the combination of investigational agents occurring during the priming week and first cycle of combination treatment (first 5 weeks) in phase I of the trial.
A study participant will be considered evaluable for a DLT if at least 2 doses of nivolumab and 4 doses of entinostat were administered during the first 5 weeks (5 weeks normally incorporate the priming week and 1 cycle of planned combination treatment). Participants who discontinue treatment or have treatment delays preventing them from receiving the above defined minimal amount of treatment in the first cycle of combination treatment for reasons unrelated to study drug toxicity, are not evaluable for DLT and will be replaced in enrollment (maximum number of replacement subjects will be 3 per dose level). | 5 weeks |
Phase II: Best response (CR or PR) | Best response (CR or PR) will be based on RANO criteria for all primary CNS tumors and RECIST for non-CNS tumors, defined for each patient as the best response under study combination therapy during the first 6 cycles (assessment every 2 cycles).
Calcified or intra-osseous (osteo)sarcoma target lesions which were progressive before initiation of treatment and show SD on response evaluation (confirmation through a subsequent scan at least 4 weeks later) will be considered as a responder. | Change in 24 weeks |
| 評価指標 | 指標の説明 | 時間枠 |
|---|---|---|
Duration of Response (DOR) | DOR will be evaluated for all patients who experienced (confirmed) response. Starting time point will be the time when best response was determined. | Phase II: maximum of 48 weeks |
Disease Control Rate (DCR) | DCR will be evaluated in addition, also using iRECIST and iRANO. | Phase II: maximum of 48 weeks |
Stable disease (SD) | SD will be evaluated in addition, also using iRECIST and iRANO. | Phase II: maximum of 12 cycles (each cycle is 28 days) |
Progression-free survival (PFS) | The event-time endpoint PFS will be estimated using the Kaplan-Meier method, considering all the patients who started the treatment, whatever their compliance to treatment, including if the treatment was stopped prematurely for a reason other than disease progression. 95%-Confidence intervals will be provided for the Kaplan-Meier estimates. | 4 years |
Time to Response (TTR) | The event-time endpoint TTR will be estimated using the Kaplan-Meier method, considering all the patients who started the treatment, whatever their compliance to treatment, including if the treatment was stopped prematurely for a reason other than disease progression. 95%-Confidence intervals will be provided for the Kaplan-Meier estimates. | Phase II: maximum of 12 cycles (each cycle is 28 days) |
Overall Survival (OS) | The event-time endpoint OS will be estimated using the Kaplan-Meier method, considering all the patients who started the treatment, whatever their compliance to treatment, including if the treatment was stopped prematurely for a reason other than disease progression. 95%-Confidence intervals will be provided for the Kaplan-Meier estimates. | Phase II: maximum of 48 weeks |
Immune related Response Rate (RR) measured by iRECIST criteria and iRANO criteria | As a secondary endpoint for patients who continued treatment beyond progression in case of clinical benefit, response as assessed by iRECIST or iRANO will be performed. | Phase II: maximum of 48 weeks |
Maximum Plasma Time (Tmax) | Time to reach the maximum concentration (hr). | one week |
Maximum Plasma Concentration (Cmax) | The peak plasma concentration of a drug after Administration (ng/mL) | one week |
Half-life | The time required for the concentration of the drug to reach half of its original value (hr) | one week |
Area under the curve (AUC) | The integral of the concentration-time curve (ng/mL·hr) | one week |
total Clearance (CI/F) | The total body clearance will be equal to the renal clearance + hepatic clearance + lung clearance (L/h/m²) | one week |
Children and adolescents with refractory/relapsed/progressive high-risk
- CNS tumors: medulloblastoma, ependymoma, ATRT, ETMR, pediatric high grade glioma (including DIPG) or other pediatric embryonal CNS tumors OR
- solid tumors: neuroblastoma, nephroblastoma, rhabdoid tumor, embryonal or alveolar rhabdomyosarcoma, other embryonal small round blue cell tumors including pediatric type (bone) sarcoma or other pediatric type solid tumors OR
- Children and adolescents with newly diagnosed high grade glioma (HGG) in the context of a constitutional mismatch repair deficiency syndrome after maximum safe surgical resection with no established standard of care treatment option with curative intention available. In addition in France: ineligible to radiotherapy
No standard of care treatment available
Age at registration ≥ 2 to ≤ 21 years
Molecular analysis for biomarker identification (SNV load, MYC/N amplification, high TILs or TLS positive) in laboratories complying with DIN EN ISO/IEC 17025 or similar via INFORM molecular diagnostic platform or equivalently valid molecular pipeline
Biomarker determined using whole exome sequencing (SNV load), whole genome- or whole exome sequencing (MYC/N amplification), IHC (high TILs or TLS positive)
In case molecular analysis was not performed via INFORM Registry molecular pipeline: transfer of molecular data (whole exome sequencing)
Time between biopsy/puncture/resection of the current refractory/relapsed/progressive tumor and registration ≤ 24 weeks. In patients receiving therapy not impacting biomarker stratification, time between biopsy/puncture/resection of the current refractory/relapsed/progressive tumor and registration of ≤ 36 weeks is allowed
Disease that is measurable as defined by RANO criteria or RECIST v1.1 (as appropriate).
Life expectancy > 3 months, sufficient general condition score (Lansky ≥ 70 or Karnofsky ≥ 70). Transient states like infections requiring antibiotic treatments can be accepted, and also stable disabilities resulting from disease/surgery (hemiparesis, amputations etc.) can be accepted and will not be considered for Lansky/Karnofsky assessments.
Laboratory requirements:
Hematology:
- absolute granulocytes ≥ 1.0 × 109/l (unsupported)
- platelets ≥ 100 × 109/l & stable
- hemoglobin ≥ 8 g/dl or ≥ 4.96 mmol/L
Biochemistry:
- Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
- AST(SGOT) ≤ 3.0 x ULN
- ALT(SGPT) ≤ 3.0 x ULN
- serum creatinine ≤ 1.5 x ULN for age
ECG: normal QTc interval according to Bazett formula < 440ms
Patient is able to swallow oral study medication
Ability of patient and/or legal representative(s) to understand the character and individual consequences of clinical trial
Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to initiation of treatment. Sexually active women of childbearing potential must agree to use acceptable and appropriate contraception during the study and for at least 6 months after the last study treatment administration. Sexually active male patients must agree to use a condom during the study and for at least 3 months after the last study treatment administration.
Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
Before patient screening and registration, written informed consent, also concerning data and blood transfer, must be given according to ICH/GCP, and national/local regulations.
No prior therapy with the combination of immune checkpoint inhibitors and HDACi
Phase I: molecular analysis performed and biomarker status known (mutational load, high TILs or TLS positive AND MYC(N) amplification status).
Phase II: molecular analysis performed, biomarker status known (mutational load, high TILs or TLS positive AND MYC(N) amplification status) and stratification according to the following criteria:
- Group A: high mutational load (defined as > 100 somatic SNVs/exome) based on whole exome sequencing OR
- Group C: Focal MYC(N) amplification based on whole genome sequencing or whole exome sequencing ot ATRT-MYC subgroup OR
- Group E: high TILs or TLS positive (defined as cells per mm² > 600 or presence of tertiary lymphoid structure) based on IHC analysis.
Patients with CNS tumors or metastases who are neurologically unstable despite adequate treatment (e.g. convulsions).
Patients with low-grade gliomas or tumors of unknown malignant potential are not eligible
Evidence of > Grade 1 recent CNS hemorrhage on the baseline MRI scan.
Participants with bulky CNS tumor on imaging are ineligible; bulky tumor is defined as:
- Tumor with any evidence of uncal herniation or severe midline shift
- Tumor with diameter of > 6 cm in one dimension on contrast-enhanced MRI
- Tumor that in the opinion of the investigator, shows significant mass effect
Previous allogeneic bone marrow, stem cell or organ transplantation
Diagnosis of immunodeficiency
Diagnosis of prior or active autoimmune disease
Evidence of interstitial lung disease
Any contraindication to oral agents or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the investigator, would preclude adequate absorption.
Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid \[qualitative\]). Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody \[HBc Ab\] and absence of HBsAg) are eligible. HBV DNA test must be performed in these patients prior to study treatment. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
Clinically significant, uncontrolled heart disease
Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery, but for these procedures, a 48 hour interval must be maintained before the first dose of the investigational drug is administered.
Any anticancer therapy (e.g., chemotherapy, HDACi (including valproic acid), DNA methyltransferase inhibitors, other immunotherapy, targeted therapy, biological response modifiers, endocrine anticancer therapy or radiotherapy) within 2 weeks or at least 5 half- lives (whichever is longer) of study drug administration.
Radiologically confirmed radiotherapy induced pseudoprogression in CNS tumors
Traditional herbal medicines; these therapies are not fully studied and their use may result in unanticipated drug-drug interactions that may cause or confound the assessment of toxicity. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the- counter medicine or herbal product. For information on CYP substrates and P-gp inhibitors or inducers see section 5.8.
History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form (including benzamide) of the investigational medicinal product
Participation in other ongoing clinical trials.
Pregnant or lactating females.
Presence of underlying medical condition (e.g. gastrointestinal disorders or electrolyte disturbances) that in the opinion of the Investigator or Sponsor could adversely affect the ability of the subject to comply with or tolerate study procedures and/or study therapy, or confound the ability to interpret the tolerability of combined administration of entinostat and nivolumab in treated subjects
Patients receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids (up to 5 mg/m2/day prednisone equivalent) may be approved after consultation with the Sponsor. No patient will be allowed to enroll in this trial more than once.
University Hospital HeidelbergGerman Cancer Research CenterNew South Wales
Victoria
Western Australia