| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Malignancies carrying a genetic alteration of ALK, MET or ROS1 |
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| E.1.1.1 | Medical condition in easily understood language |
| Genetic alteration in tumor tissue leading to a magnified growth of tumor cells. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
• Stratum 1b: to determine the antitumor activity of crizotinib monotherapy at 165 mg/m2 BID in patients with relapsed/refractory ALCL with ALK rearrangements. These data will also be added to a pooled analysis with two additional studies that will be provided.
• Stratum 2: to determine the RP2D of crizotinib in combination with temsirolimus in patients with relapsed/refractory RMS or NBL with ALK or MET aberrations defined as ALK or MET rearrangements, activating mutations, or ALK/MET amplification.
• Stratum 3: to determine the safety and preliminary activity of crizotinib monotherapy at 280 mg/m2 BID in patients with ALK/ROS1/MET aberrant malignancies defined as either ALK rearrangements, activating mutations, amplification; MET amplification; or ROS1 rearrangements, activating mutations or amplification. Once stratum 1b is completed, patients with ALK rearranged relapsed or refractory ALCL will be eligible to enroll in stratum 3.
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| E.2.2 | Secondary objectives of the trial |
• To assess safety of crizotinib monotherapy (stratum 1b and 3).
• To evaluate the ocular toxicity in patients receiving crizotinib monotherapy (165 mg/m2 BID or 280 mg/m2 BID, stratum 1b or 3).
• To assess the occurrence of hypergonadotrophic hypogonadism and hypogonadotrophic hypogonadism in boys ≥ 13 years old (stratum 1b, 2, 3).
• To study the preliminary activity of crizotinib in combination with temsirolimus in patients with relapsed/refractory NBL or RMS (stratum 2).
• To study pharmacokinetics of single-agent crizotinib, and crizotinib in combination with temsirolimus to study potential drug-drug interactions
• To assess the activity of crizotinib monotherapy or in combination with temsirolimus in terms of:
• duration of response,
• best overall response,
• time to response
• time to progression and progression free survival
• overall survival
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria stratum 1b
• Histologically or cytologically confirmed diagnosis of relapsed/refractory ALCL, including first relapse
• Age at enrolment ≥1 year of age and ≤ 21 years
• Lansky play score > 60%; or Karnofsky performance status > 60%.
• Target gene aberration as defined as:
o The t(2;5) translocation or rearrangement t(1;2), t(2;3), inv(2), t(2;22). This should be apparent in all tumor cells
This can be proven by ALK- immunohistochemistry, FISH or NGS
• Life expectancy 12 weeks
• Disease involvement :
o Measurable disease defined as at least one nodule with a longest diameter greater than 1.5 cm (pediatric NHL response criteria) [Sandlund 2015]
• Adequate hematological function, unsupported, last platelet transfusion > 72 hours and off colony stimulating factors:
o ANC ≥0.75x109/L and platelets ≥ 75x109/L for pts without bone marrow involvement. Note: for patients in the UK the eligibility criteria require at least ≥1.0x109/L
o Patients with bone marrow involvement will be allowed to enter with ANC
≥0.5x109/L and platelets ≥50x109/L
stratum 2:
• Histologically or cytologically confirmed diagnosis of relapsed/refractory NBL or RMS
• Age at enrolment ≥1 year of age and ≤21 years
• Lansky play score > 60%; or Karnofsky performance status > 60%.
• Target gene aberration as defined as:
o A point mutation in the kinase domain of ALK that results in an amino-acid change, and is not a known polymorphism
o An amplification of the ALK gene, defined as ≥ 9 copies per cell, or 4 copies per haploid genome. When assessed by FISH, ALK amplification must be observed in focal clusters of tumor cells (not only single cells) or in more than one-third of the tumor cells
o A rearrangement in >15% of the tumor cells (by break apart FISH-assay or RNAseq)
OR
o An amplification of the MET-gene, defined as of ≥5 MET signals per tumor cell (by break apart FISH)
o A MET mutation, defined as the presence of a somatic mutation (Direct, bi- directional sequencing of exon 16-19 of MET )
o TFE3 rearrangement, define as at least 15% of cells rearranged (FISH home- made break-apart TFE3 probe set: RP11-344N17 and RP11-552J9)
• Life expectancy 12 weeks
• Disease involvement:
o For dose escalation measurable and non-measurable disease is allowed
o For dose expansion measurable disease is mandated, except for neuroblastomas where MIBG or FDG avidity is sufficient
o For RMS: Measurable disease defined as per RECIST 1.1 [Eisenhauer 2009]
o For NBL: Measurable disease defined as per RECIST 1.1 or evaluable disease (I123 MIBG or FDG uptake with or without bone marrow metastases).
stratum 3:
• Histologically confirmed diagnosis of other solid tumor or lymphomas other than ALCL that is relapsed or refractory to standard therapy, or patients with newly diagnosed IMT for whom surgery may not be feasible for close proximity to vital structures, without prior tumor-shrinkage and no other feasible options are available as per local standard of care.
Of note: when stratum 1b is completed, ALCL patients will be eligible to enroll into stratum 3 according to the criteria described in this section on stratum 3 eligibility.
• Age at enrolment ≥1 year of age and ≤ 21 years
• Lansky play score > 60%; or Karnofsky performance status > 60%.
• Target gene aberration as defined as: For ALK:
o A point mutation in the kinase domain of ALK that results in an amino-acid change, and is not a known polymorphism
o An amplification of the ALK gene, defined as ≥ 9 copies per cell, or 4 copies per haploid genome. When assessed by FISH, ALK amplification must be observed in focal clusters of tumor cells (not only single cells) or in more than one-third of the tumor cells
o A rearrangement in >15% of the tumor cells (by break apart FISH-assay or RNAseq)
For ROS1
o A ROS1 rearrangement in > 15% of the tumor cells (by break apart FISH- assay or RNAseq)
For MET
o An amplification of the MET-gene, defined as of ≥5 MET signals per tumor
cell (by break apart FISH)
o A MET mutation, defined as the presence of a somatic mutation (Direct, bi- directional sequencing of exon 16-19 of MET )
o TFE3 rearrangement, define as at least 15% of cells rearranged (FISH home- made break-apart TFE3 probe set: RP11-344N17 and RP11-552J9)
• Life expectancy 12 weeks
• Disease involvement:
o Measurable disease according to RECIST 1.1 [Eisenhauer 2009]
o Or, measurable disease as defined as at least one nodule with a longest diameter greater than 1.5 cm (pediatric NHL response criteria) [Sandlund 2015]
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| E.4 | Principal exclusion criteria |
• Other serious illnesses or medical conditions
• Active uncontrolled infection
• History of allergic reactions to the compounds or their solvents
• Patients with untreated CNS metastases and/or primary CNS tumors and/or meningeal lymphoma involvement, defined as CNS3 status (patients with CNS2 are eligible)
• Concurrent use of drugs or foods that are known potent CYP3A4 inducers or inhibitors, CYP3A4 substrates with narrow therapeutic indices as well as medication with known QT-prolongation see Appendix 2
• Any of the following within the 3 months prior to starting study treatment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure or cerebrovascular accident including transient ischemic attack.
• Use of live vaccines within 30 days of first dosing
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of crizotinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome)
• Not able to comply with scheduled follow-up and with management of toxicity.
• A cardiac shortening fraction < 29%
• Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any
grade, or QTcF interval >470 msec.
• History of extensive disseminated/bilateral or known presence of grade 3 or 4 interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, and pulmonary fibrosis, but not history of prior radiation pneumonitis.
• Evidence of active graft-vs-host disease (GVHD)
• less than 3 months post-allogeneic HSCT.
• Receiving GVHD prophylaxis
• Pregnant or lactating females
• Spinal cord compression unless treated with the patient attaining good pain control and stable or recovered neurologic function.
• Prior malignancy (other than current malignancy): patients will not be eligible if they have evidence of active malignancy (other than non-melanoma skin cancer or localized cervical cancer, or localized and presumed cured prostate cancer) within the last 3 years.
• Carcinomatous meningitis or leptomeningeal disease
stratum 2 as above +:
• Patients with neuroblastoma and bone marrow disease only, are excluded.
stratum 3 as above + • Receiving GVHD prophylaxis.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Stratum 1b and 3: Overall response rate (ORR) defined as the percentage of patients achieving complete (CR) and partial responses (PR) by IPNHL (International Pediatric revised Response Criteria for Malignant Lymphoma) for ALCL, by RECIST version 1.1 (Response Criteria for Solid Tumors) for solid tumors after 2 courses (8 weeks) relative to the appropriate response evaluable set.
• Stratum 2: Dose Limiting Toxicities (DLT) during the first cycle of crizotinib, in combination with temsirolimus.
• Stratum 3: Adverse events (AEs) during crizotinib monotherapy, as characterized by type, frequency, severity (graded using CTCAE v4.03), timing and relation to the study therapy, during the first and subsequent courses of therapy.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Assessed during the first 28 days of treatment
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| E.5.2 | Secondary end point(s) |
overall response, defined as the number of patients achieving complete and partial response during the total study period and time to best response.
• Plasma concentration time profiles, PK parameters, including but not limited to AUClast, AUCtau, Cmin, Cmax, and Tmax for crizotinib and temsirolimus.
• Stratum 1b: adverse events (AEs) during crizotinib monotherapy, as characterized by type, frequency, severity (graded using CTCAE v4.03), timing and relation to the study therapy, during the first and subsequent courses of therapy.
• Stratum 1b: Overall response rate (ORR) defined as the percentage of patients achieving complete (CR) and partial responses (PR) by IWG criteria after 2 courses (8 weeks) relative to the appropriate response evaluable set.
• Stratum 2: adverse events (AEs) during crizotinib and temsirolimus therapy, as characterized by type, frequency, severity (graded using CTCAE v4.03), timing and relation to the study therapy, after the first course of therapy.
• To collect the results from ophthalmologic examinations and ocular AEs in patients exposed to crizotinib.
• The number (and percentage) of boys ≥ 13 years old (stratum 1b, 2, 3) with hypergonadotrophic hypogonadism or hypogonadotrophic hypogonadism.
• Duration of response (DOR), defined as the time between achieving response (CR or PR) after the start of study treatment and documented disease progression, relapse or death
• Progression free survival (PFS) is defined as the time interval between the start of treatment and the date of confirmed disease progression or death, whichever comes first.
• Overall survival (OS), defined as time to death following start of study treatment.
Archival tumor sample and/or fresh frozen and/or embedded tumor sample taken prior to enrolment will be analyzed centrally to confirm ALK, MET, ROS1 aberration using next generation sequencing (NGS), and if applicable FISH.
• When available paired samples before and after 2 cycles of treatment will be analyzed to show inhibition of ALK and the PI3K/AKT pathways.
• When available, paired bone marrow sample in patients with neuroblastoma enrolled at the Royal Marsden Hospital before and after 2 cycles of treatment will be stored for neuroblastic cells isolation and target inhibition studies.
• PRP samples before and 5 hours after the start of drug(s) administration at the beginning of cycle 1 will be analyzed for target inhibition in PRP as surrogate tissue. This will be repeated on day 8 of cycle 1 (pre-dose only) day 1 of cycle 2 (pre-dose only) and day 1 of cycle 3 (pre-dose only).
• Tumor cf-DNA will be analyzed throughout the study protocol in order to assess pre- treatment, in-treatment and post-treatment tumor genome alterations and to compare those to the aberrations found in the primary tumor samples.
• For ALCL sequential blood samples will be assessed for minimal disseminated disease by using NPM-ALK PCR as a marker for minimal residual disease and ALK antibodies concentrations |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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 |
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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.8.3 |
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 | 20 |
| 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 |
| Belgium |
| Denmark |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Spain |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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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| All patients will have a safety evaluation visit at 1 month after the last dose of crizotinib. Here AEs and SAEs will be assessed and concomitant medication recorded, this will be repeated at 3 months. Moreover, there will be a 2 year follow up, 3 monthly, by telephone. The trial is ended when this follow up is completed for all patients. |
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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 | 8 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
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