assignment

Recruiting

Phase 1B Evaluation of Crizotinib Alone or with Temsirolimus in Pediatric ALK, ROS1, or MET-Positive Malignancies

Trial ID: 2023-504880-18-00
Protocol: CRISP ITCC-053
Sponsor: Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

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Diseases & Conditions

Anaplastic large cell lymphoma T- and null-cell types Neuroblastoma Rhabdomyosarcoma Inflammatory myofibroblastic tumour

Objectives

The primary objective of this study is to determine the recommended phase 2 dose (RP2D) of crizotinib in combination with temsirolimus. Additionally, the study aims to evaluate the safety and preliminary activity of single-agent crizotinib in tumors that are positive for ALK, MET, or ROS1. This is clinically relevant as it seeks to establish an effective dosing regimen and assess the therapeutic potential of crizotinib, both alone and in combination, in pediatric patients with specific genetic markers, which could lead to more targeted and effective treatments for these malignancies. Secondary objectives include:

To study the preliminary activity of crizotinib in combination with temsirolimus for relapsed or refractory ALK-positive rhabdomyosarcoma or neuroblastoma.
To study the pharmacokinetics of single-agent crizotinib, and crizotinib in combination with temsirolimus, as well as the potential drug-drug interactions between crizotinib and temsirolimus.
To assess the best overall response and overall survival.
To assess the duration of response, time to progression, and progression-free survival.

Participants

The clinical trial involves a total of 10 participants diagnosed with conditions such as Inflammatory Myofibroblastic Tumors (IMT), other ALK/ROS1/MET-positive malignancies, Neuroblastoma (NBL), Rhabdomyosarcoma (RMS), and Anaplastic Large Cell Lymphoma (ALCL). The study population includes both male and female subjects, aged between 1 and 21 years, who are considered part of a vulnerable population. Participants were selected based on a histologically or cytologically confirmed diagnosis of relapsed or refractory conditions, with specific genetic aberrations such as ALK, MET, or ROS1 mutations. The trial requires a Lansky play score greater than 60% or a Karnofsky performance status greater than 60%, and a life expectancy of at least 12 weeks. Participants must not have received prior therapy directly targeting ALK, ROS1, or MET, and any previous systemic anticancer therapy must have been completed at least two weeks before the initiation of the study medication. The trial includes individuals who have not undergone treatment with any other investigational drug within the past two weeks or major surgery. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the safety and efficacy of crizotinib as a single agent or in combination with temsirolimus in pediatric patients with ALK, ROS1, or MET-positive malignancies. This study is a phase 1B trial, employing a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The trial is expected to run from April 18, 2018, to December 31, 2029, with the primary objective of determining the recommended phase 2 dose (RP2D) of crizotinib in combination with temsirolimus, as well as assessing the safety and preliminary activity of single-agent crizotinib in the specified tumor types. Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and specific genetic aberrations. Following successful screening, participants will be enrolled and randomized into different strata based on their specific tumor type and genetic profile. The study will include regular follow-up visits to monitor safety, efficacy, and pharmacokinetic parameters, with assessments conducted at predefined intervals. The end-of-study visit will occur after the completion of the treatment period or upon early termination. The expected length of participant involvement will vary depending on individual response and tolerance to the treatment, with a minimum life expectancy requirement of 12 weeks for eligibility. Conditions that may lead to early termination from the study include the occurrence of dose-limiting toxicities, disease progression, or withdrawal of consent. The primary endpoints include dose-limiting toxicities during the first cycle of treatment and overall response rate, while secondary endpoints encompass overall response rate after two courses, best overall response rate, plasma concentration time profiles, pharmacokinetic parameters, progression-free survival, and overall survival.

Treatment

The clinical trial involves the administration of Torisel, a pharmaceutical product containing the active substance temsirolimus. Torisel is provided as a 30 mg concentrate and solvent for solution for infusion, intended for intravenous infusion. The product is manufactured by Pfizer Europe MA EEIG and is authorized under the marketing authorization number EU/1/07/424/001. The administration of Torisel is conducted via intravenous infusion, and the dosing schedule is determined based on the trial protocol. Participant compliance is monitored through regular assessments and documentation of infusion sessions. Another experimental medication used in the trial is Crizotinib, which is available in multiple pharmaceutical forms, including hard capsules, oral solution, and granules in capsules for opening. Crizotinib is administered orally, and the specific form used may vary depending on the participant's needs and the trial phase. The hard capsules are marketed under the name XALKORI, available in 200 mg and 250 mg dosages, with marketing authorization numbers EU/1/12/793/001 and EU/1/12/793/004, respectively. The oral solution and granules in capsules for opening are identified by the sponsor product code PF-02341066. Crizotinib is produced by Pfizer Inc. and is used as a single agent or in combination with temsirolimus, depending on the trial arm. The dosing schedule for Crizotinib is determined by the trial protocol, and participant adherence is monitored through pill counts and patient diaries. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial documentation. The trial focuses on evaluating the safety and efficacy of the experimental medications in pediatric patients with ALK, ROS1, or MET positive malignancies. Compliance with the dosing regimen is crucial, and participants are closely monitored to ensure adherence to the trial protocol.

Efficacy

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the evaluation of Dose Limiting Toxicities (DLT) during the first cycle of crizotinib in combination with temsirolimus for stratum 2, and the overall response rate for stratum 1b and 3. Secondary endpoints will focus on the overall response rate for stratum 2, defined as the number of patients achieving complete and partial responses by disease after two courses (8 weeks). Additionally, the best overall response rate will be determined by the best reported overall lesions response at different evaluation time points from the start of study treatment until disease progression. Further secondary endpoints include the analysis of plasma concentration time profiles and pharmacokinetic (PK) parameters for crizotinib and temsirolimus. Progression-free survival (PFS) and overall survival will also be measured. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial to determine the safety and preliminary activity of single-agent crizotinib in ALK, MET, or ROS1 positive tumors. The trial is designed to provide comprehensive data on the efficacy of the treatment regimen in pediatric patients with ALK, ROS1, or MET positive malignancies.

Inclusion and Exclusion Criteria

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Inclusion Criteria

1b en 2:Histologically or cytologically confirmed diagnosis of relapsed/refractory ALCL, including first relapse, NBL or RMS 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.when stratum 1b is completed, ALCL patients will be eligible to enroll into stratum 3 • 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 stratum 1b: The t(2;5) translocation or rearrangement t(1;2), t(2;3), inv(2), t(2;22). proven by ALK- immunohistochemistry, FISH or NGS stratum 2: A point mutation in the kinase domain of ALK, An amplification of the ALK gene,rearrangement in >15% of the tumor cells or An amplification of the MET-gene,MET mutation, TFE3 rearrangement, stratum 3: o A point mutation in the kinase domain of ALK, or MET mutation o An amplification of the ALK or MET gene, o A ROS1 or TFE3 rearrangement in > 15% of the tumor cells • Life expectancy ≥ 12 weeks • Disease involvement : o stratum 1b Measurable disease defined as at least one nodule with a longest diameter greater than 1.5 cm (pediatric NHL response criteria) stratum 2: For dose escalation measurable and non-measurable disease is allowed; For dose expansion measurable disease is mandated, except for neuroblastomas where MIBG or FDG avidity is sufficient stratum 3:Measurable disease according to RECIST 1.1 Or, measurable disease as defined as at least one nodule with a longest diameter greater than 1,5 cm • Any previous systemic anticancer therapy must have been completed at least 2 weeks prior to initiation of study medication • No prior therapy directly targeting ALK or ROS1 or MET • No treatment with any other investigational drug within the past 2 weeks or major surgery Male and female patients of child-bearing potential must agree to use an effective method for males and a highly effective method for females

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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 CYP3A4 substrates with narrow therapeutic indices as well as medication with known QT‐prolongation, • Use of drugs or foods that are known strong CYP3A4 inhibitors within 7 days prior to the first dose of crizotinib. •Use of drugs that are known strong CYP3A4 inducers within 12 days prior to first dose of crizotinib.• 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., • 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.,• 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 Plus for stratum 2:, • Patients with neuroblastoma and bone marrow disease only, are excluded.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Denmark	Recruiting	18 Apr 2018	8
Finland	Recruiting	18 Apr 2018	3
France	Recruiting	18 Apr 2018	10
Germany	Recruiting	18 Apr 2018	9
Italy	Recruiting	18 Apr 2018	9
The Netherlands	Recruiting	18 Apr 2018	—
Norway	Recruiting	18 Apr 2018	4
Slovakia	Not Yet Recruiting	18 Apr 2018	4
Spain	Recruiting	18 Apr 2018	10
Netherlands	—	—	15

Sites & Investigators

Research sites

Hospital Vall d’Hebron Virgen del Rocío University Hospital Charite Universitaetsmedizin Berlin KöR Helsinki University Central Hospital

Investigators

Beatriz V. M.Adela C. N.Judith L. P.Michela C.

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name	Role in Trial	Formulation	Administration	Max Daily Dose	Treatment Duration	EU MP Number
CRIZOTINIB	Test	GRANULES IN CAPSULES FOR OPENING	ORAL	—	—	PRD11510980
CRIZOTINIB	Test	CAPSULE, HARD	ORAL	—	—	PRD10935852
XALKORI 200 mg hard capsules	Test	HARD CAPSULES	ORAL	—	—	PRD3362134
CRIZOTINIB	Test	GRANULES IN CAPSULES FOR OPENING	ORAL	—	—	PRD11513016
CRIZOTINIB	Test	GRANULES IN CAPSULES FOR OPENING	ORAL	—	—	PRD11510964
CRIZOTINIB	Test	ORAL SOLUTION	ORAL	—	—	PRD10935862
XALKORI 250 mg hard capsules	Test	HARD CAPSULES	ORAL	—	—	PRD3362133
Torisel 30 mg concentrate and solvent for solution for infusion	Test	CONCENTRATE AND SOLVENT FOR SOLUTION FOR INFUSION	INTRAVENIOUS INFUSION	—	—	PRD6538648

Conditions Studied in This Trial

Interventions Studied in This Trial

vaccines

Crizotinib

14 trials

Also investigated for

Non-small cell lung cancer 3 Non-small cell lung cancer stage IIIB 2 Uveal melanoma 2 Anaplastic large cell lymphoma T- and null-cell types 1

vaccines

Temsirolimus

1 trial

Also investigated for

Anaplastic large cell lymphoma T- and null-cell types 1 Inflammatory myofibroblastic tumour 1 Neuroblastoma 1 Rhabdomyosarcoma 1