Phase 2 Study Assessing Efficacy and Safety of Crizotinib in Patients Harboring an Alteration on ALK, MET or ROS1

NCT ID: NCT02034981

Last Updated: 2024-02-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 246 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-08-31
• Study Completion Date: 2023-12-06

Brief Summary

This is a biology driven, trans-tumoral, multicentric phase II trial assessing the efficacy and the safety of the targeted agent crizotinib as a monotherapy in 23 cohorts of patients with identified activating molecular alterations in the crizotinib target genes. A cohort is defined by a pathology and a crizotinib-target alteration (eg gastric cancer with MET amplification).

For each cohort a two-stage design will be implemented. In the situation where expected accrual allows for a sufficient number of patients to be accrued, the alpha and beta errors will be fixed at 10%. However, in very rare diseases, such as inflammatory myofibroblastic tumor (IMT), neuroblastoma, glioblastoma, and rhabdomyosarcoma (RMS), it is anticipated that the target number may not be achievable in a reasonable timeframe; for these cohorts, the alpha and beta errors will be fixed at 15%. Consequently three different statistical designs will be a priori considered according to the expected response rate and incidence.

Detailed Description

Twenty cohorts are identified, a cohort being defined as [one pathology, one target alteration] such as [gastric cancer with MET amplification (6%)].

One cohort will be dedicated to miscellaneous, very rare pediatric diseases identified through INCa platforms or pan-genome programs (e.g. MOSKIDO, IGR) and will recruit up to 10 patients.

Two cohorts will be dedicated to a couple of diseases harbouring at least one specific alteration in one crizotinib target, same or different from those listed above, e.g. in AXL gene, arising from pan-genome trials.

1. ALCL, adults and children, ALK-translocated

2. Colorectal cancer, adults, ALK-translocated

3. Colorectal cancer, adults, MET amplified

4. Colorectal cancer, adults, MET mutated

5. NSCLC, adults, MET amplified

6. NSCLC, adults, ROS1-translocated

7. Breast cancer, adults, ALK-translocated

8. Gastric cancer, adults, MET amplified

9. Cholangiocarcinoma, adults, ROS1-translocated

10. Ovarian cancer, adults, MET amplified

11. Clear cell renal cell carcinoma, adults, ALK-translocated

12. Clear cell renal cell carcinoma, adults, ALK-amplified

13. Papillary renal cell carcinoma, adults, MET mutated (+ MET amplified)

14. Hepatocarcinoma, adults, MET amplified

15. Neuroblastoma, adults and children, ALK-amplified + ALK mutated

16. IMT, adults and children, ALK-translocated

17. Rhabdomyosarcoma (alveolar and embryonal), adults and children, ALK-amplified

18. Glioblastoma, adults, MET amplified. This cohort will only be open after amendment

19. Anaplastic thyroid cancer, adults, ALK mutated

20. Thyroid cancer (follicular + medullary + papillary), adults, MET mutated

21. Miscellaneous rare pediatric diseases associated to at least one specific alteration in one crizotinib target, same or different from those listed above

22. One another pathology associated to at least one specific alteration in one crizotinib target, same or different from those listed above.

23. One another pathology associated to at least one specific alteration in one crizotinib target, same or different from those listed above.

Conditions

Hematologic Cancers; Solid Tumors; Metastatic Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

CRIZOTINIB

All eligible patients entering the study will receive oral crizotinib as monotherapy

Group Type: EXPERIMENTAL

Crizotinib

Intervention Type: DRUG

Patients will receive oral crizotinib, daily continuously, until progression or unacceptable toxicity develops.

-250 mg twice daily for adults ≥ 18 years of age

• 280 mg/m² twice daily for children and adolescents aged from 1 to 17 (except ALCL).
• 165 mg/m² twice daily for ALCL patients aged from 1 to 17.

Interventions

Crizotinib

Patients will receive oral crizotinib, daily continuously, until progression or unacceptable toxicity develops.

-250 mg twice daily for adults ≥ 18 years of age

• 280 mg/m² twice daily for children and adolescents aged from 1 to 17 (except ALCL).
• 165 mg/m² twice daily for ALCL patients aged from 1 to 17.

Intervention Type: DRUG

Other Intervention Names

XALKORI

Eligibility Criteria

Inclusion Criteria

• Male and female ≥ 1 year of age
• unresectable locally advanced or metastatic malignant tumor of any histological type (but NSCLC with an ALK translocation) and not amenable to any other validated therapeutic option. ( for pediatrics a relapse after a first well-conducted standard treatment or a situation without any standard treatment and a survival <10%).
• one proven specific alterations among ALK, MET, RON and ROS1 genes determined on the primary and/or the metastatic lesion
• Measurable disease according to RECIST 1.1
• For patients with primary cerebral tumors (adults or children), measurable disease defined by bi-dimensional measurements : two perpendicular diameters of at least 10 mm on CT or MRI scan, outside of a previously radiated field within the last 3 months, to observe pseudoprogression
• hematologic function (ANC ≥ 1.0x10⁹/L, platelets ≥ 75x10⁹/L, platelets ≥ 50x10⁹/L for ALCL with bone marrow involved ; platelets ≥ 100x10⁹/L for primary or secondary cerebral tumors; Hb ≥ 8g/L), renal function (creat cl ≥ 50 mL/min Cockcroft and Gault) and hepatic function (serum bilirubin ≤ 1.5x ULN unless due to Gilbert's syndrome ; ASAT and ALAT ≤ 5x ULN if liver metastasis or ≤ 3x ULN if liver metastasis with advanced fibrosis (FibroTest>0.48) or ≤ 3x ULN without liver metastasis)
• normal values for calcium, magnesium and potassium levels
• able to swallow and retain oral medication
• ECOG Performance Status of 0 to 2, or Karnofsky scale > 50 % or Lansky Play scale (< 12 years) > 50%, (for CNS tumors, the neurological deficiency due to the disease itself)
• Life expectancy ≥ 3 months

Exclusion :

• NSCLC patients ALK translocations
• Patient eligible for a clinical trial with an anticancer drug (including crizotinib) targeting the same molecular alteration open to accrual in France.
• alteration limited to an overexpression of ALK, MET, RON, ROS1 or any other crizotinib-target. Only patients with ALCL are eligible if ALK is positive by immunohistochemistry
• Patients with primary or secondary central nervous system disease
• Previous treatment with crizotinib
• Major surgery or tumor embolization within 4 weeks and minor surgery within 2 weeks prior to the initiation of the study drug. Brain surgery is excluded within 4 weeks prior to starting crizotinib for primary or secondary cerebral tumors
• Patients with other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study, such as, but not limited to :

• Within the 3 months prior to starting study treatment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, or cerebrovascular accident including transient ischemic attack
• Ongoing congestive heart failure
• Congenital long QT syndrome
• Heart rate ≤ 45 beats/minute
• Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, or with QTcF interval >470 msec
• For patients with a cerebral disease (primary or secondary) : uncontrolled hypertension [defined as SBP of ≥ 140 mmHg or DBP of ≥ 90mmHg]
• extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease, including pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, and pulmonary fibrosis, but not prior radiation pneumonitis
• Spinal cord compression unless treated with the patient attaining good pain control and stable or recovered neurologic function
• Carcinomatous meningitis or leptomeningeal disease
• HIV-positive, active hepatitis A, B or C, or latent hepatitis B or C, or any other uncontrolled infection
• Other severe acute or chronic medical or psychiatric conditions, or end stage renal disease on hemodialysis or laboratory abnormalities
• For patients with a cerebral disease, detection on the MRI or the CTscan of a real arteriovenous malformation, or an untreated intracranial aneurysm, or a cavernous angioma, or an amyloid angiopathy, or any new or significant (≥ grade 2) intratumoral bleeding other than microbleeds on T2* weighted MRI in the previous 14 days before treatment initiation, or a recent and untreated subdural effusion.
• Patients using non-substitutable drugs that are potent CYP3A4 inhibitors, or potent CYP3A4 inducers
• Patients using non-substitutable drugs that are CYP3A4 substrates with narrow therapeutic indices
• Patients with cerebral disease using anti-platelet drugs or anticoagulant agents are not eligible if those treatments can not be stopped 7 days before day1.
• Patients with altered mental status or with psychological, familial, sociological or geographical condition potentially hampering compliance
• Individual deprived of liberty or placed under the authority of a tutor.

• Minimum Eligible Age: 1 Year
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute, France

OTHER_GOV

Sponsor Role: collaborator

Fondation ARC

OTHER

Sponsor Role: collaborator

Pfizer

INDUSTRY

Sponsor Role: collaborator

UNICANCER

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Gilles VASSAL

Role: PRINCIPAL_INVESTIGATOR

Gustave Roussy, Villejuif

Locations

Gustave Roussy

Villejuif, Île-de-France Region, France

Countries

France

References

Brugieres L, Cozic N, Houot R, Rigaud C, Sibon D, Arfi-Rouche J, Bories P, Cottereau AS, Delmer A, Ducassou S, Garnier N, Lamant L, Leruste A, Millot F, Moalla S, Morschhauser F, Nolla M, Pagnier A, Reguerre Y, Renaud L, Schmitt A, Simonin M, Verschuur A, Hoog Labouret N, Mahier Ait Oukhatar C, Vassal G. Efficacy and safety of crizotinib in ALK-positive systemic anaplastic large-cell lymphoma in children, adolescents, and adult patients: results of the French AcSe-crizotinib trial. Eur J Cancer. 2023 Sep;191:112984. doi: 10.1016/j.ejca.2023.112984. Epub 2023 Jul 17.

Reference Type: DERIVED

PMID: 37549532 (View on PubMed)

Aparicio T, Cozic N, de la Fouchardiere C, Meriaux E, Plaza J, Mineur L, Guimbaud R, Samalin E, Mary F, Lecomte T, Gomez-Roca C, Haineaux PA, Gratet A, Selves J, Menu Y, Colignon N, Johnson L, Legrand F, Vassal G. The Activity of Crizotinib in Chemo-Refractory MET-Amplified Esophageal and Gastric Adenocarcinomas: Results from the AcSe-Crizotinib Program. Target Oncol. 2021 May;16(3):381-388. doi: 10.1007/s11523-021-00811-8. Epub 2021 Apr 13.

Reference Type: DERIVED

PMID: 33847874 (View on PubMed)

Moro-Sibilot D, Cozic N, Perol M, Mazieres J, Otto J, Souquet PJ, Bahleda R, Wislez M, Zalcman G, Guibert SD, Barlesi F, Mennecier B, Monnet I, Sabatier R, Bota S, Dubos C, Verriele V, Haddad V, Ferretti G, Cortot A, De Fraipont F, Jimenez M, Hoog-Labouret N, Vassal G. Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSe phase II trial. Ann Oncol. 2019 Dec 1;30(12):1985-1991. doi: 10.1093/annonc/mdz407.

Reference Type: DERIVED

PMID: 31584608 (View on PubMed)

Other Identifiers

2013-000885-13

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

UC-0105/1303

Identifier Type: -

Identifier Source: org_study_id