Clinical trial NCT02813135: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors
Official title: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Pediatric Cancer
Keywords: Children
Adolescents
Young adults
Recurrent malignancies
Refractory malignancies
Lead sponsor: Gustave Roussy, Cancer Campus, Grand Paris
Sponsor class: OTHER
Collaborators: name: National Cancer Institute, France
First posted: 2016-06-24
Enrollment: 455
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Recommended phase II dose (RP2D)
timeFrame: During the first cycle
measure: Maximum Tolerated Dose (MTD)
timeFrame: During the first cycle
measure: Objective Response Rate (ORR)
timeFrame: During treatment period
Secondary outcomes:
measure: Pharmacokinetics (PK)
timeFrame: Depending on the treatment arm
measure: Progression Free Survival (PFS)
timeFrame: From treatment initiation until the date of first documented progression or death
measure: Evaluation of duration of response (DoR)
timeFrame: Between the first document response and the time of first documented progression
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Villejuif
country: France
facility: Gustave Roussy
state: Val De Marne
city: Angers
country: France
facility: CHU Angers
city: Bordeaux
country: France
facility: CHU Pellegrin
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Hôpital de La Timone
city: Nantes
country: France
facility: CHU Nantes
city: Paris
country: France
facility: Institut Curie
city: Paris
country: France
facility: Hôpital Armand Trousseau
city: Milan
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
city: Torino
country: Italy
facility: Ospedale Infantile Regina Margherita
city: Utrecht
country: Netherlands
facility: Prinses Maxima Centrum
city: Barcelona
country: Spain
facility: Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital del Nino Jesus
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
city: Newcastle
country: United Kingdom
facility: Royal Victoria Infirmary
city: Sutton
country: United Kingdom
facility: Pediatric and Adolescent Oncology The Royal Marsden Hospital
Study officials:
affiliation: Gustave Roussy, Cancer Campus, Grand Paris
name: Birgit Geoerger, MD
role: STUDY_CHAIR
References:
citation: Berlanga P, Pierron G, Lacroix L, Chicard M, Adam de Beaumais T, Marchais A, Harttrampf AC, Iddir Y, Larive A, Soriano Fernandez A, Hezam I, Chevassus C, Bernard V, Cotteret S, Scoazec JY, Gauthier A, Abbou S, Corradini N, Andre N, Aerts I, Thebaud E, Casanova M, Owens C, Hladun-Alvaro R, Michiels S, Delattre O, Vassal G, Schleiermacher G, Geoerger B. The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies. Cancer Discov. 2022 May 2;12(5):1266-1281. doi: 10.1158/2159-8290.CD-21-1136.
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citation: Pasqualini C, Rubino J, Brard C, Cassard L, Andre N, Rondof W, Scoazec JY, Marchais A, Nebchi S, Boselli L, Grivel J, Aerts I, Thebaud E, Paoletti X, Minard-Colin V, Vassal G, Geoerger B. Phase II and biomarker study of programmed cell death protein 1 inhibitor nivolumab and metronomic cyclophosphamide in paediatric relapsed/refractory solid tumours: Arm G of AcSe-ESMART, a trial of the European Innovative Therapies for Children With Cancer Consortium. Eur J Cancer. 2021 Jun;150:53-62. doi: 10.1016/j.ejca.2021.03.032. Epub 2021 Apr 20.
citation: Rossoni C, Bardet A, Geoerger B, Paoletti X. Sequential or combined designs for Phase I/II clinical trials? A simulation study. Clin Trials. 2019 Dec;16(6):635-644. doi: 10.1177/1740774519872702. Epub 2019 Sep 20.