CABozantinib in Non-Small Cell Lung Cancer (NSCLC) Patients With MET Deregulation

Phase 2

• Conditions: Non-Small Cell Lung Cancer
• Interventions: Drug: Cabozantinib

• Registration Number: NCT03911193
• Lead Sponsor: Fondazione Ricerca Traslazionale

Brief Summary

This is a multicenter, single arm, phase II study evaluating efficacy in terms of RR in a cohort of NSCLC with MET amplification or MET exon 14 skipping mutation pre-treated or not with MET inhibitors.

Detailed Description

The study population will include NSCLC patients with MET amplification or MET exon 14 skipping mutation pre-treated or not with MET inhibitors. Elegible NSCLC patients with MET exon 14 skipping mutations or MET amplification will be treated with open label orally cabozantinib 60 mg/daily, cycles each 28 days. Disease evaluation will be performed every two months (8 weeks). Patients will be treated with cabozantinib until disease progression, unacceptable toxicity or patient refusal.Treatment will be continued until disease progression, unacceptable toxicity or patient refusal. Treatment beyond disease progression is allowed if considered appropriate by the investigator.

Study Timeline

• Study Start: 2018-09-21
• Status Verified: 2019-03
• Study First Submitted: 2019-03-28
• Study First Submitted QC: 2019-04-08
• Last Update Submitted: 2019-04-08
• Study First Posted: 2019-04-11
• Last Update Posted: 2019-04-11
• Primary Completion: 2020-09
• Study Completion: 2020-09

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 25

Inclusion Criteria

1. Citological or histological diagnosis of non-small-cell-lung cancer (NSCLC) stage III B (not suitable for local treatments with curative intent) or stage IV.

2. Tissue samples available for MET analysis (archivial tissue or tissue collected at study entry); patients without archival tumor tissue or refusing new biopsy at study entry, are eligible if MET mutation is detected in cf-DNA

3. Presence of MET mutations (exon 14 skipping mutation ONLY) detected in tissue or cf-DNA at the local lab or in the central lab or MET amplification (MET/CEP7 ratio > 2.2) detected in the central lab ONLY.

4. Measurable disease according to RECIST criteria version 1.1

5. At least 1 prior line of standard therapy (chemotherapy and/ or immunotherapy)

6. Performance status 0-1 (ECOG)

7. Age ≥18 years

8. Patients potentially fertile using adequate methods of contraception in order to avoid childbearing. Contraceptive methods must be respected by male and female patients and their partners during study treatment period and at least 4 months after completing therapy

9. Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to enrollment:

   1. ANC ≥ 1500 cells/μL without granulocyte colony-stimulating factor support

   2. Platelet count ≥ 100,000/μL without transfusion

   3. Hemoglobin ≥ 9.0 g/dL Patients may be transfused to meet this criterion

   4. AST, ALT, and alkaline phosphatase ≤ 2.5 × ULN, with the following exceptions:

      • Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN
      • Patients with documented liver or bone metastases: alkaline phosphatase ≤ 5 × ULN.

   5. Serum bilirubin ≤ 1.25 × ULN

   6. Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled

   7. Calculated creatinine clearance (CRCL) ≥ 45 mL/min or calculated CRCL must be ≥ 60 mL/min

10. Patient compliance to the study procedure

11. Written informed consent

Exclusion Criteria

1. Tissue sample not available in patients without MET exon 14 skipping mutation detected in cf-DNA
2. No possibility to assess MET status
3. Absence of any measurable disease according to RECIST criteria
4. Co-existence of driver events, including EGFR mutations, KRAS mutations, ALK rearrangements or ROS-1 rearrangements
5. No prior therapy
6. Concomitant chemotherapy or immunotherapy or radiotherapy
7. Symptomatic brain metastasis
8. Uncontrolled significant inter-current or recent illness, including cardio-vascular disorders and gastro-intestinal disorders
9. Major surgery within 2 months before first dose of study treatment
10. Concomitant anti-coagulation with oral anti-coagulants or plated inhibitors
11. History of significant bleeding, trachea-bronchial tree/major blood vessels invading tumors, cavity pulmonary lesions and GI disorders associated with a risk of perforation or fistula formation
12. Diagnosis of another cancer in the last 3 years, except for in situ carcinoma of cervix, breast and bladder or skin carcinoma (squamous or basalioid)
13. Pregnancy or breastfeeding

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cabozantinib	Cabozantinib	Elegible NSCLC patients with MET exon 14 skipping mutations or MET amplification will be treated with open label orally cabozantinib 60 mg/daily, cycles each 28 days.

Primary Outcome Measures

Name	Time	Method
Response Rate (RR) (complete + partial responses)	Up to 36 months	RR will be evaluated by investigators according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Partial and complete responses will be confirmed following RECIST criteria 1.1. Disease evaluation will be performed every two months (8 weeks).

Secondary Outcome Measures

Name	Time	Method
Progression free survival (PFS)	Up to 36 months	Disease evaluation will be performed every 8 weeks
Disease Control Rate (DCR: stable disease + partial response + complete response)	Up to 36 months	Disease evaluation will be performed every 8 weeks
Overall survival (OS)	Up to 36 months	Disease evaluation will be performed every 8 weeks
Exploratory biomarkers	Up to 36 months	At baseline, at the first disease evaluation and at progression of disease a blood sample will be collected for biomarkers analyses

Trial Locations

Locations (20)

Azienda Ospedaliero- Universitaria di Parma; 🇮🇹 Parma, PR, Italy

A.O. S.M. Misericordia; 🇮🇹 Perugia, PG, Italy

Azienda Ospedaliero Universitaria Pisana; 🇮🇹 Pisa, PI, Italy

Irccs Irst; 🇮🇹 Meldola, FO, Italy

A.O. "S.Giuseppe Moscati"; 🇮🇹 Avellino, AV, Italy

A.O. Papardo; 🇮🇹 Messina, ME, Italy

IRCCS Oncologico Giovanni Paolo II; 🇮🇹 Bari, BA, Italy

Istituto Europeo di Oncologia; 🇮🇹 Milano, MI, Italy

A.O.U. Careggi; 🇮🇹 Firenze, FI, Italy

Ospedale Infermi Rimini; 🇮🇹 Rimini, FO, Italy

Ospedale San Gerardo; 🇮🇹 Monza, MI, Italy

AOU Policlinico di Modena; 🇮🇹 Modena, MO, Italy

Istituto Oncologico Veneto; 🇮🇹 Padova, PD, Italy

Casa di Cura La Maddalena; 🇮🇹 Palermo, PA, Italy

AUSL Reggio Emilia- IRCCS Arcispedale S.M. Nuova; 🇮🇹 Reggio Emilia, RE, Italy

Fondazione Policlinico Gemelli; 🇮🇹 Roma, RM, Italy

Istituto Nazionale Tumori Regina Elena; 🇮🇹 Roma, RO, Italy

A.O.U. S. Luigi Gonzaga; 🇮🇹 Orbassano, Torino, Italy

AUSL della Romagna; 🇮🇹 Ravenna, Italy

Azienda Ospedaliero Universitaria Integrata di Verona; 🇮🇹 Verona, Italy