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 |
|
E.1.1.1 | Medical condition in easily understood language |
Genetic alteration in tumor tissue leading to a magnified growth of tumor cells. |
|
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 1: to determine the RP2D of crizotinib in combination with vinblastine in
relapsed/refractory ALCL with ALK aberrations, defined as ALK translocations
* Stratum 2: to determine the RP2D of crizotinib in combination with temsirolimus in patients
with relapsed/refractory RMS or NBL with ALK aberrations defined as ALK translocations,
activating mutations, or ALK amplification
* Stratum 3: to determine the safety and preliminary activity of single‐agent crizotinib for
ALK/ROS1/MET aberrant malignancies defined as either ALK translocations, activating
mutations, amplification, MET amplification or ROS1 translocations, activating mutations or
amplification |
|
E.2.2 | Secondary objectives of the trial |
* To study the preliminary activity of crizotinib in combination with standard relapse
chemotherapy for ALCL, or crizotinib in combination with temsirolimus for NBL and RMS.
* To study pharmacokinetics of single‐agent crizotinib, and crizotinib in combination with
vinblastine or temsirolimus to study potential drug‐drug interactions
* To assess the duration of response, time to progression, progression free survival and overall
survival |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Stratum 1:
•Histologically or cytologically confirmed diagnosis of ALCL
•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 translocation in >15% of the tumor cells (by break apart FISH‐assay)
•Disease involvement:
o For dose escalation measurable and non measurable disease is allowed
o For does expansion measurable disease is mandated
o Measurable disease is defined as at least one nodule with a longest diameter
greater than 1.5 cm (pediatric NHL response criteria)
Stratum 2:
•Histologically or cytologically confirmed diagnosis NBL or RMS
•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 translocation in >15% of the tumor cells (by break apart FISH‐assay)
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, bidirectional
sequencing of exon 16‐19 of MET)
o TFE3 rearrangement, define as at least 15% of cells rearranged (FISH homemade
break‐apart TFE3 probe set: RP11‐344N17 and RP11‐552J9)
•Disease involvement:
o For dose escalation measurable and non‐measurable disease is allowed
o For does expansion measurable disease is mandated, except for
neuroblastomas where MIBG disease is sufficient
o For RMS: Measurable disease defined as per RECIST 1.1 with a target lesion
of at least 10 mm
o For NBL: Measurable disease defined as per RECIST 1.1 or evaluable disease
(I123 MIBG uptake with or without bone marrow metastases)
Stratum 3:
•Histologically or cytologically confirmed diagnosis of other solid tumor or lymphomas
other than ALCL (at initial diagnosis) that is relapsed or refractory to standard therapy. Or
patients with newly diagnosed IMT in whom radical surgery is deemed infeasible or will
result in significant morbidity/mutilation
•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 translocation in >15% of the tumor cells (by break apart FISH‐assay)
For ROS1
o A ROS1 rearrangement in >15% of the tumor cells (by break apart FISHassay)
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, bidirectional
sequencing of exon 16‐19 of MET )
o TFE3 rearrangement, define as at least 15% of cells rearranged (FISH homemade
break‐apart TFE3 probe set: RP11‐344N17 and RP11‐552J9)
•Disease involvement:
o Measurable disease according to RECIST 1.1 with a target lesion of at least
10 mm
o Or, measurable disease as defined as at least one nodule with a longest
diameter greater than 1.5 cm (pediatric NHL response criteria)
•No prior therapy directly targeting ALK or ROS1or MET |
|
E.4 | Principal exclusion criteria |
• Other serious illnesses or medical conditions
• Current uncontrolled infection
• History of allergic reactions to the compounds or their solvents
• Patients with known 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 as
well as medication with known QT‐prolongation
• 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.
• No evidence of active graft‐vs‐host disease (GVHD) and at least 3 months post‐allogeneic
HSCT. Must not receive GVHD prophylaxis.
• For patients with childbearing potential, a negative test for pregnancy and agreement to use
effective contraceptive measures is required before entry on study.
Plus for stratum 1:
• Patients with ALCL and skin lesions only, are excluded
Plus for stratum 2:
• Patients with neuroblastoma and bone marrow disease only, are excluded. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Dose Limiting Toxicities (DLT) during the first cycle of crizotinib, in combination with either vinblastine, temsirolimus
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Assessed during the first 28 days of treatment
|
|
E.5.2 | Secondary end point(s) |
• Overall response rate defined as the number of patients achieving complete and partial
responses by disease after 2 courses (8 weeks).
• Overall response rate defined as the number of patient achieving complete and partial
response during the total study period.
• Plasma concentration time profiles, PK parameters, including but not limited to AUClast,
AUCtau, Cmin, Cmax, Tmax, Racc, and T1/2,acc for crizotinib, temsirolimus and vinblastine.
• Progression‐free survival (PFS) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Stratum 1: at the end of cycle 2, then every 4 months, and after a year every 6 months.
• Solid tumors (stratum 2 and 3): at the end of cycle 2 and then every other cycle for stratum 2 and every 3 cycles for stratum 3.
• Stratum 1, 2 and 3: PR and CR will have to be confirmed by repeated imaging at least 4 weeks after observation of response.
• Blood samples for PK analysis: at the start of the 2nd cycle at the day that vinblastine (stratum 1) or temsirolimus (stratum 2) are also administered.
• PFS: the time interval between the date of enrolment and the date of confirmed disease progression or death (events) whatever the cause, whichever comes first. If neither event has been observed, then the patient is censored at the date of the last follow-up examination. |
|
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 |
|
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 | 33 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
|
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. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
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 | 5 |