Therapy Study Based on Molecular Changes in Refractory or Recurrent Tumors

Denmark, France, Germany, Italy, Netherlands, Spain, United Kingdom (ICTRP)

ICTRP Trial ID
NCT02813135 (ICTRP)

Official title (approved by ethics committee)
AcSé-ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (BASEC)

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

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

Disease under investigation
Children, Adolescents and Young Adults With Refractory or Recurrent Malignancies (ICTRP)

Intervention under investigation
Drug: Ribociclib;Drug: Topotecan;Drug: Temozolomide;Drug: AZD1775;Drug: Carboplatin;Drug: Olaparib;Drug: Irinotecan;Drug: Nivolumab;Drug: Enasidenib;Drug: Lirilumab (ICTRP)

Type of trial
Interventional (ICTRP)

Trial design
Allocation: Non-Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)

Inclusion/Exclusion 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 st (ICTRP)

not available

Primary and secondary end points
Objective tumor response;Time to progression (ICTRP)

not available

Registration date
16.06.2016 (ICTRP)

Incorporation of the first participant
03.08.2016 (ICTRP)

Secondary sponsors
National Cancer Institute, France (ICTRP)

Additional contacts
Birgit Geoerger, MD;Birgit Geoerger, MD, birgit.geoerger@gustaveroussy.fr, 1 42 11 4661, Gustave Roussy, Cancer Campus, Grand Paris, (ICTRP)

Secondary trial IDs
2016/2396, 2016-000133-40 (ICTRP)

Results-Individual Participant Data (IPD)
not available

Further information on the trial
https://clinicaltrials.gov/show/NCT02813135 (ICTRP)