European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (ESMART)

Gustave Roussy

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Pediatric Cancer

Treatments: Drug: Cytarabine; Drug: Temozolomide; Drug: Capmatinib; Drug: Vistusertib; Drug: Fadraciclib; Drug: Lirilumab; Drug: Vinorelbine; Drug: Futibatinib; Drug: Peposertib; Drug: Irinotecan; Drug: Selumetinib; Drug: Olaparib; Drug: Enasidenib; Drug: Capivasertib; Drug: Nivolumab; Drug: Ceralasertib; Drug: Everolimus; Drug: Cyclophosphamide; Drug: Avelumab; Drug: Carboplatin; Drug: Adavosertib; Drug: Ribociclib; Drug: Topotecan; Drug: Dexamethasone

Study type: Interventional

Funder types: Other

Identifiers

NCT02813135

2016-000133-40

2024-514791-40-00 (EU Trial (CTIS) Number)

2016/2396 (Other Identifier)

Details and patient eligibility

About

This proof-of-concept platform trial is designed to cover the targeting of several survival pathways in oncogenesis that are currently not adequately employed for pediatric patients in Europe (Geoerger 2017; Geoerger 2019).

The aims of the trial are:

1. To determine the recommended phase II dose (RP2D) of a specific anticancer agent and/or a relevant combination in a pediatric population, to document its tolerability and
2. To explore first signals of activity in a molecularly enriched study population.

Full description

The first molecular profiling protocols have been launched in Europe (MOSCATO-01 (Geoerger 2014), MAPPYACTS, INFORM, iTHER, SM-PAEDS, etc.) determining multiple actionable alterations in pediatric recurrent cancers. Increasingly, stratified approaches are being implemented to enrich clinical trials of molecularly targeted agents and possibly improve outcomes in specific populations i.e. a molecularly enriched/predictive biomarker-driven approach. The diversity and heterogeneity of the detected molecular alterations and the low number of pediatric patients mandate an adapted, innovative trial design for the attributed treatment options in order to satisfy the current unmet medical need.

This basket trial is designed to cover the targeting of several survival pathways in oncogenesis that are currently not adequately employed for pediatric patients in Europe.

Enrollment: 472 estimated patients

Sex: All

Ages: Under 18 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Patients must be diagnosed with a haematologic or solid tumor malignancy that has progressed despite standard therapy, or for which no effective standard therapy exists.

2. Age < 18 years at inclusion; patients 18 years and older may be included after discussion with the sponsor if they have a pediatric recurrent/refractory malignancy.

3. Patient must have had advanced molecular profiling (i.e. WES/WGS +/- RNAseq) of their recurrent or refractory tumor i.e. at the time of disease progression/relapse; exceptionally patients with advanced molecular profiling at diagnosis may be allowed.

4. Evaluable or measurable disease as defined by standard imaging criteria for the patient's tumor type (RECIST v1.1, RANO criteria for patients with HGG, INRC criteria for patients with NB, Leukemia criteria, etc.).

5. Patients with relapsed or refractory leukemia are eligible for this study.

6. Performance status: Karnofsky performance status (for patients >12 years of age) or Lansky Play score (for patients ≤12 years of age) ≥ 70%. Patients who are unable to walk because of paralysis or stable neurological disability, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

7. Life expectancy ≥ 3 months

8. Adequate organ function:

   Hematologic criteria (Leukemia patients are excluded from hematological criteria):

   • Peripheral absolute neutrophil count (ANC) ≥ 1000/μL(unsupported)
   • Platelet count ≥ 100,000/μL (unsupported)
   • Hemoglobin ≥ 8.0 g/dL (transfusion is allowed)

   Cardiac function:

   • Shortening fraction (SF) >29% (>35% for children < 3 years) and left ventricular ejection fraction (LVEF) ≥50% at baseline, as determined by echocardiography (mandatory only for patients who have received cardiotoxic therapy).
   • Absence of QTc prolongation (QTc > 450 msec on baseline ECG, using the Fridericia correction [QTcF formula]) or other clinically significant ventricular or atrial arrhythmia.

   Renal and hepatic function:

   • Serum creatinine ≤ 1.5 x upper limit of normal (ULN) for age
   • Total bilirubin ≤ 1.5 x ULN
   • Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤ 2,5 x ULN; aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT ≤ 2,5 x ULN except in patients with documented tumor involvement of the liver who must have AST/SGOT and ALT/SGPT ≤ 5 x ULN.

9. Able to comply with scheduled follow-up and with management of toxicity.

10. Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours 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 males patients must agree to use condom during the study and for at least 6 months (7 months for arm J) after the last study treatment administration. Acceptable contraception are defined in CTFG Guidelines "Recommendations related to contraception and pregnancy testing in clinical trials"

11. For all oral medications patients must be able to comfortably swallow capsules (except for those for which an oral solution is available); nasogastric or gastrostomy feeding tube administration is allowed only if indicated.

12. Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study-specific screening procedures are conducted according to local, regional or national guidelines.

13. Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.

Exclusion criteria

1. Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or require increasing doses of corticosteroids or local CNS-directed therapy to control their CNS disease. Patients on stable doses of corticosteroids for at least 7 days prior to receiving study drug may be included.
2. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
3. Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality, unstable ischemia,congestive heart failure within 12 months of screening)
4. Active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
5. Presence of any ≥ CTCAE grade 2 treatment-related toxicity with the exception of alopecia, ototoxicity or peripheral neuropathy.
6. Systemic anticancer therapy within 21 days of the first study dose or 5 times its half-life, whichever is less.
7. Previous myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks of the first study drug dose
8. Allogeneic stem cell transplant within 3 months prior to the first study drug dose. Patients receiving any agent to treat or prevent graft-versus host disease (GVHD) post bone marrow transplant are not eligible for this trial.
9. Radiotherapy (non-palliative) within 21 days prior to the first dose of drug (or within 6 weeks for therapeutic doses of MIBG or craniospinal irradiation).
10. 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.
11. Currently taking medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes (Refer to Appendix 8).
12. Currently taking medications that are mainly metabolized by CYP3A4/5, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp (MDR1), BCRP, OATP1B1, OATP1B3, OCT1 and OCT2 and have a low therapeutic index that cannot be discontinued at least 7 days or 5 x reported elimination half-life prior to start of treatment with any of the investigational drugs and for the duration of the study (Refer to Appendix 9).
13. Known hypersensitivity to any study drug or component of the formulation.
14. Pregnant or nursing (lactating) females.
15. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

472 participants in 18 patient groups

Arm A. Ribociclib + Topotecan and Temozolomide

Experimental group

Description:

Topotecan iv QD and temozolomide capsules orally QD Days 1 to 5; Ribociclib capsules or oral solution orally QD from Day 6 to 20 of a 28 day cycle.

Treatment:

Drug: Topotecan

Drug: Ribociclib

Drug: Temozolomide

Arm B. Ribociclib + Everolimus

Experimental group

Description:

Ribociclib capsules or oral solution orally QD for 21 days of each 28 day cycle; Everolimus orodispersible tablets orally QD for 28 days.

Treatment:

Drug: Ribociclib

Drug: Everolimus

ARM C. Adavosertib + Carboplatin

Experimental group

Description:

Adavosertib capsules orally BID 3 days on / 4 days off in week 1; Carboplatin iv QD AUC 5 on Day 1 of a 21 day cycle.

Treatment:

Drug: Adavosertib

Drug: Carboplatin

Arm D. Olaparib + Irinotecan

Experimental group

Description:

Olaparib tablets orally BID on Day 1-10 of a 21 day cycle Irinotecan iv QD on Day 4-8 of a 21 day cycle.

Treatment:

Drug: Irinotecan

Drug: Olaparib

Arm E. Vistusertib single agent

Experimental group

Description:

Vistusertib tablets orally BID 2 days on/5 days off per week of a 28 day cycle.

Treatment:

Drug: Vistusertib

Arm F. Vistusertib + Topotecan and Temozolomide

Experimental group

Description:

Topotecan iv QD and temozolomide capsules orally QD Days 1 to 5; Vistusertib tablets orally BID 3 days on/4 days off per week of a 28 day cycle.

Treatment:

Drug: Topotecan

Drug: Vistusertib

Drug: Temozolomide

Arm G. Nivolumab + Cyclophosphamide +/- Radiotherapy

Experimental group

Description:

Nivolumab iv QD every 2 weeks of a 28 day cycle (Days 1 and 15); Cyclophosphamide tablets or oral solution orally BID, 1 week on/1 week off; Palliative irradiation/radiofrequency/cryotherapy starting 2 weeks after the first nivolumab injection.

Treatment:

Drug: Cyclophosphamide

Drug: Nivolumab

Arm H. Selumetinib + Vistusertib

Experimental group

Description:

Selumetinib capsules twice daily on a continous administration. Vistusertib orally twice daily on an intermittent schedule : 2 days on / 5 days off per week of a 28 day cycle.

Treatment:

Drug: Selumetinib

Drug: Vistusertib

Arm I. Enasidenib

Experimental group

Description:

Enasidenib tablets or sprinkle solution orally on a continuous dosing once daily (QD) per 28 day cycle.

Treatment:

Drug: Enasidenib

Arm J. Lirilumab + Nivolumab

Experimental group

Description:

Nivolumab iv QD on Day 1 and 15 of a 28 day cycle; Lirilumab iv QD on Day 1 of a 28 day cycle

Treatment:

Drug: Lirilumab

Drug: Nivolumab

Arm K. Fadraciclib (CYC065) + Temozolomide

Experimental group

Description:

Fadraciclib iv QD on Day 1 (+/- 15) of a 28 day cycle Temozolomide capsules orally QD on Day 1-5 of a 28 day cycle

Treatment:

Drug: Fadraciclib

Drug: Temozolomide

Arm L. Fadraciclib (CYC065) + Cytarabine

Experimental group

Description:

Fadraciclib iv QD on Day 1 (+/- 15) of a 28 day cycle Cytarabine iv or sc on Day 2-5 and Day 8-11 of a 28 day cycle

Treatment:

Drug: Fadraciclib

Drug: Cytarabine

Arm M. Ribociclib + Everolimus +/- Dexamethasone

Experimental group

Description:

Ribociclib capsules or tablets orally QD on Day 1-21 of a 28 day cycle. Everolimus dispersible tablets orally QD on a continuous dosing per 28 day cycle. For patients with leukemia and lymphoma: Dexamethasone orally or iv on Day 1-7 of each 28 day cycle. For patients with ALL, AML and Non-Hodgkin Lymphoma (NHL), Intrathecal chemotherapy will be administered additionally as per standard practice depending on CNS status.

Treatment:

Drug: Dexamethasone

Drug: Ribociclib

Drug: Everolimus

Arm N. Ceralasertib (AZD6738) + Olaparib

Experimental group

Description:

Olaparib tablets orally BID per 28 days Ceralasertib tablets QD or BID per 28 day cycle

Treatment:

Drug: Ceralasertib

Drug: Olaparib

Arm O. Futibatinib (TAS-120)

Experimental group

Description:

Futibatinib tablets orally on a continuous dosing QD per 28 day cycle

Treatment:

Drug: Futibatinib

Arm P. Capmatinib (INC280) + Everolimus

Experimental group

Description:

Capmatinib tablets orally on a continuous dosing BID per 28 day cycle. Everolimus dispersible tablets orally QD on a continuous dosing per 28 day cycle.

Treatment:

Drug: Everolimus

Drug: Capmatinib

Arm Q. Peposertib + Avelumab and Metronomic Temozolomide

Experimental group

Description:

Peposertib tablets orally on a continuous dosing BID per 28 day cycle Avelumab IV QD on Day 1 and Day 15 of a 28 day cycle Temozolomide capsules orally QD 5 days/week of a 28 day cycle

Treatment:

Drug: Peposertib

Drug: Avelumab

Drug: Temozolomide

Arm R. Capivasertib + metronomic Vinorelbine

Experimental group

Description:

Capivasertib tablets orally BID on Day 1-4/week (4 days on/3 days off, every week) of a 28 day cycle. Vinorelbine soft capsules orally once daily on Day 1, 3 and 5/week of a 28 day cycle.

Treatment:

Drug: Vinorelbine

Drug: Capivasertib