E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced and/or metastatic malignant tumor (anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, papillary renal cell carcinoma type 1, alveolar soft part sarcoma, clear cell sarcoma or alveolar rhabdomyosarcoma) deemed incurable by conventional surgery, radiotherapy, systemic therapy or any other means. |
|
E.1.1.1 | Medical condition in easily understood language |
Local diagnosis of locally advanced and/or metastatic sub types of lymphoma, RCC and soft tissue sarcoma deemed incurable by surgery, radiotherapy, systemic therapy or any other means. |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10065867 |
E.1.2 | Term | Alveolar rhabdomyosarcoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10002227 |
E.1.2 | Term | Anaplastic large cell lymphoma T- and null-cell types |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10067918 |
E.1.2 | Term | Inflammatory myofibroblastic tumor |
E.1.2 | System Organ Class | 100000072955 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10001882 |
E.1.2 | Term | Alveolar soft part sarcoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067946 |
E.1.2 | Term | Renal cell carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065865 |
E.1.2 | Term | Clear cell sarcoma |
E.1.2 | System Organ Class | 100000143827 |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The study will primarily assess the efficacy of crizotinib in a variety of tumors with alterations in ALK
and/or MET pathways. The targeted patient population will include patients with tumors harboring specific
alterations leading to ALK and/or MET activation, where tyrosine kinase inhibitors against these targets
have not yet been adequately explored. |
|
E.2.2 | Secondary objectives of the trial |
To study the specificity of the kinase inhibitor for tumors in all cohorts by explorative comparison of treatment results in patients with the same disease type with and without genetic alterations in ALK and/or MET.
To investigate sensitive and reliable methodologies for patient screening for such defects, to be potentially cross-validated and further developed by an accredited laboratory in later steps, based on prospectively collected biological material from this trial.
To explore the potential value of selected biomarkers to study the pharmacological effects of crizotinib.
To explore whether molecularly driven, high quality multi-tumor screening Phase 2 trials are feasible in a multi-institutional, multidisciplinary setting, when screening and treatment are performed by EORTC (+:- additional selected sites).
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Step 1 registration:
♦ Local diagnosis of locally advanced and/or metastatic malignant
tumor (ALCL, IMFT, PRCC, ASPS, CCSA, ARMS) deemed incurable by
conventional surgery, radiotherapy, systemic therapy or any other
means.
♦ Mandatory availability for shipment of formalin-fixed, paraffin embedded, tumor-containing, non-returnable tissue blocks from primary tumor and/or metastatic site ( Slides not accepted). Information on previous histopathology reports and previous molecular analysis will be entered in an eCRF, to accompany the tissue samples.
♦ Written informed consent for central collection of tissue block and any other trial-specific procedures must be obtained from the patient
allowing for collection storage and analysis of tissue and screening
procedures prior to registration.
Step 2 histopathology central confirmation:
♦ Confirmation of receipt of tissue block and accompanying required
local information, and confirmation that tissue block contains tumor
tissue (quality assurance) by central biorepository through EORTC, as
well as central pathology confirmation, are required before starting the patient screening (step 3) according to chapter 6.4.
Step 3 enrollment:
♦ Measurable disease according to RECIST 1.1 with target lesion of at
least 20 mm (or 10 mm on spiral CT scans) and presence of at least one RECIST-measurable lesion outside of a previously radiated field or
potential palliative irradiation fields.
♦ Patients with brain metastases are eligible if treated and/or
neurologically stable with no ongoing requirement for corticosteroids
(off steroids for at least 2 weeks) and not taking contraindicated
medications . Absence of spinal cord compression unless treated with
the patient attaining good pain control and stable or recovered neurologic function.
♦ Minimum age 1 year, no upper age limit.
♦ Eastern Cooperative Oncology Group (ECOG) performance status 0-2 or Lansky Play scale >= 50 for children aged 1 to 12 yo.
♦ Adequate hematological function: ANC ≥ 1 x 109/L, platelets ≥ 30 x
109/L and hemoglobin ≥ 8 g/dL.
♦ Adequate renal function:
A) For patients up to 21 years old:
The Schwartz formula should be used for Clearance Creatinine [mL/min/1.73 m2 = F x Height (cm) x 88.4/creatinine (blood) in µmol/L. ClCr of 80-140 mL/min/1.73 m2 is considered as normal range
- F = 0.55 for boys 1-15 yo
- F = 0.70 for boys 16-21 yo
- F = 0.55 for girls 1-21 yo
B) For patients 21 years or older: serum creatinine ≤ 2 x ULN.
♦ Adequate liver function: Bilirubin ≤ 1.5 x ULN unless due to Gilbert's syndrome (status of the disease documented by repeated laboratory values with slight increase in bilirubin without any other known causes). AST and ALT ≤ 2.5 x ULN in the absence of liver metastases and ≤ 5 x UNL if liver function abnormalities are due to the underlying malignancy.
♦ Clinically normal cardiac function based on the institutional lower limit of normal LVEF (assessed by MUGA or ECHO) and normal 12 lead ECG.
♦ Machine-read ECG with QTcF interval ≤470 msec.
♦ Women of child bearing potential with negative serum pregnancy test
♦ All patients of childbearing/reproductive potential using adequate
birth control
Disease specific inclusion criteria for patients with anaplastic large cell
lymphoma (ALCL)
♦ Patient may have received previous systemic treatment, surgery
and/or radiotherapy for localized, locally advanced or advanced disease.
♦ Patient must have received previous systemic chemotherapy (usually a CHOP-like multidrug combination, if not medically contraindicated, with or without monoclonal antibodies), and may not qualify for further conventional therapy with curative intent.
♦ No pretreatment limitations (including autologous or allogeneic stem cell- or bone marrow transplantation), provided all other patient
selection criteria are met.
Disease-specific inclusion criteria for patients with inflammatory
myofibroblastic tumor (IMFT), papillary renal cell carcinoma type 1
(PRCC),clear cell sarcoma (CCSA),alveolar soft part sarcoma (ASPS),
alveolar rhabdomyosarcoma (ARMS)
♦ Patient may have received previous systemic treatment, surgery
and/or radiotherapy for localized, locally advanced or metastatic
disease.
♦ No mandatory pretreatment.
♦ No pretreatment limitations, provided all other patient selection
criteria are met. |
|
E.4 | Principal exclusion criteria |
♦ Malignant meningitis or leptomeningeal disease.
♦ Any previous systemic anticancer therapy in the last 4 weeks prior to
initiation of study medication.
♦ Treatment with any other investigational drug within the past 4 weeks or within less than 4 half-life times of the investigational drug before treatment with crizotinib (whatever is the longest period).
♦ Prior therapy directly targeting ALK and/or MET, Previous treatment
with crizotinib.
♦ Major surgery in past 4 weeks prior to initiation of study medication.
♦ Prior palliative radiotherapy 24 hrs prior to initiation of study
medication, and minor surgical procedures two weeks prior to the
initiation of study medication.
♦ Other previous and active malignancy for the last three years with the exception of non-melanoma skin cancer, localized cervical cancer,
localized and presumably cured prostate cancer or adequately treated
basal or squamous cell skin carcinoma.
♦ Laboratory abnormalities that would impart, in the judgment of the
investigator and/or sponsor, excess risk associated with study
participation or study drug administration.
♦ All related adverse events from previous therapies must have
recovered to ≤ Grade 1 (except alopecia). No persistence of adverse
events from prior anti-cancer therapy deemed clinically relevant.
♦ Acute or chronic severe gastrointestinal conditions such as diarrhea or ulcer.
♦ Within the three months prior to starting study treatment, no
myocardial infarction, no severe/unstable angina, no coronary/peripheral artery bypass graft, congestive heart failure or cerebrovascular accident including transient ischemic attack.
♦ Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥ 2.
♦ Uncontrolled atrial fibrillation of any grade.
♦ 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.
♦ Concurrent use of drugs or foods that are known strong CYP3A4
inhibitors, including but not limited to atazanavir, clarithromycin,
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir,
saquinavir, telithromycin, troleandomycin, voriconazole, and grapefruit or grapefruit juice (refer to section 5.6). The topical use of these medications (if appropriate), such as 2% ketoconazole cream, may be allowed.
♦ Concurrent use of drugs that are known potent CYP3A4 inducers, within 12 days prior to first dose of crizotinib including but not limited to carbamazepine, phenobarbital, phenytoin,
rifabutin, rifampin, and St. John's wort (refer to section 5.6).
♦ Use of drugs that are CYP3A4 substrates with narrow therapeutic
indices, including but not limited to pimozide, dihydroergotamine,
ergotamine, astemizole, cisapride, and terfenadine (refer to section 5.6).
♦ Other severe acute or chronic medical conditions including severe
gastrointestinal conditions such as diarrhea or ulcer) or psychiatric
conditions or end stage renal disease on hemodialysis or laboratory
abnormalities that would impact, in the judgment of the investigator
and/or sponsor, excess risk associated with study participation or study drug administration, and which would, therefore, make the patient inappropriate for study entry.
♦ Female subjects who are breast feeding
♦ Any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Response rate documented by RECIST 1.1 (with response confirmation). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
At the end of trial (per cohort). |
|
E.5.2 | Secondary end point(s) |
Safety (CTAE v 4.0)
Progression free survival
Clinical benefit, as assessed by the rate of CR+PR+ Stable Disease (SD)
Overall survival
Duration of clinical benefit |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
At the end of trial (per cohort). |
|
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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
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.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
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
|
End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol, if the trial reaches its primary endpoint
3. The database has been fully cleaned and frozen for this analysis |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |