Phase II Study With Cabozantinib in Patients With RET Positive NSCLC

Non Small Cell Lung Cancer Clinical Trial

— CRETA  

Official title:

"Phase II Study to Evaluate the Activity and Safety of Cabozantinib in Pretreated, Advanced RET-rearranged Non-small Cell Lung Cancer Patients: CRETA Trial"

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04131543
• Other study ID #: CRETA
• Status: Recruiting
• Phase: Phase 2
• Start date: August 7, 2019
• Est. completion date: August 7, 2022

Study information

• Verified date: October 2019
• Source: University of Bologna
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is aimed to explore the antitumor activity, safety and efficacy profile of cabozantinib in pretreated, advanced RET-rearranged non-small cell lung cancer patients

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 25
• Est. completion date: August 7, 2022
• Est. primary completion date: August 7, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Locally advanced, relapsed or metastatic non-small cell lung cancer - stage IIIB/IV according to 7th International Association for the Study of Lung Cancer (IASLC) classification

2. Ability to understand and willingness to sign informed consent prior to initiation of any study procedures.

3. Pathologically (histology or cytology) confirmed diagnosis of non- small cell lung carcinoma.

4. RET gene rearrangement by local laboratory analysis with an approved standard method (FISH or Next Generation Sequencing Panel). An archival tumor sample must be available for central laboratory confirmation.

5. Male or female and = 18 years of age

6. Life expectancy = 12 weeks

7. Have progressed after or during at least one standard anticancer treatment

8. Have measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1); clear radiological evidence of disease progression after first-line therapy must be documented; no previous radiotherapy on the only site of measurable or evaluable disease, unless that site had subsequent evidence of progression

9. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 1

10. Subjects must have adequate organ function including the following:

• Absolute neutrophil count > 1.5 x 10^9/L

• Platelet count > 100 x 10^9/L

• Haemoglobin > 90 g/L

• ALT < 2.5 times the upper limit of normal (ULN)

• AST < 2.5 times ULN

• Total bilirubin <1.5 times ULN

• Creatinine <1.5 times ULN concurrent with creatinine clearance > 50 ml/min (measured or calculated by Cockcroft and Gault equation, confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN)

• Lipase < 2.0 times the upper limit of normal (ULN)

11. Stable medical condition, including the absence of acute exacerbations of chronic illnesses, serious infections, or major surgery within 4 weeks before registration, and otherwise noted in other inclusion/exclusion criteria

12. Recovered (i.e., = Grade 1 toxicity) from effects of prior anticancer therapy, except alopecia

13. No radiologic or clinical evidence of acute or chronic pancreatitis

14. For Females: must be postmenopausal (defined as amenhorrea = 12 consecutive months) before the screening visit, or are surgically sterile. If they are of childbearing potential, a negative serum pregnancy test obtained within 3 days before starting study treatment has to be documented; furthermore, patients must agree to adopt 2 effective methods of contraception, at the same time, from the time of signing the informed consent form (ICF) through 4 months after the last dose of study drug.

15. For Males: even if surgically sterilized (i.e. post-vasectomy status) agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug.

16. Ability to comply with protocol requirement.

Exclusion criteria:

1. Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before randomization. Systemic treatment with radionuclides within 6 weeks before randomization. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.

2. Previous treatment with cabozantinib.

3. Gastrointestinal disorders likely to interfere with absorption of the study drug.

4. Subjects with gastrointestinal disorders associated with a high risk of perforation of fistula formation.

5. Subjects with active peptic ulcer or with a history of clinically ¿significant GI bleeding within 6 months before the first dose of study treatment.

6. Patients requiring full-dose anticoagulation therapy any time prior to enrollment.

7. Current use of aspirin, clopidogrel, ticlopidine.

8. Patients with tumors invading major pulmonary vessels and/or with cavitating pulmonary lesions.

9. Major surgery within the last four weeks. Complete wound healing from major surgery must have occurred 1 month before randomization and from minor surgery at least 10 days before randomization. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.

10. Subjects with clinical or radiological signs of pulmonary hemorrhage within 3 months before the first dose of study treatment.

11. Symptomatic CNS or leptomeningeal lesions, not previously treated with radiotherapy.

Untreated central nervous system (CNS) or leptomeningeal metastases are allowed if asymptomatic. Patients with symptomatic CNS or leptomeningeal lesions will be allowed to participate in this study if previously treated with radiotherapy and on stable dose of corticosteroids and/or anticonvulsants for > 10 days or not requiring such medication.

Radiotherapy must have been completed a minimum of 4 weeks prior to registration, and patients must have recovered from AEs related to radiotherapy to < grade 1 (except alopecia).

12. History of congenital platelet function defect.

13. Patient unable to swallow tablets

14. Corrected QT interval greater than 500 ms (Fridericia formula)

15. Clinically significant, uncontrolled heart diseases:

• Unstable angina within 6 months prior to screening

• Myocardial infarction within 6 months prior to screening

• History of documented congestive heart failure

• Uncontrolled hypertension defined by a Systolic Blood Pressure , with or without antihypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening

• Ventricular arrhythmias, Supraventricular and nodal arrhythmias not controlled with medication

• Congenital history of QT syndrome.

16. Diagnosed with or treated for another malignancy within 3 years before the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type may be enrolled in the study if they have undergone complete resection and no evidence of active disease is present.

17. Any type of systemic anticancer agent within 3 weeks of first dose of study treatment, or within 5 half- lives of the agent whichever is shorter (subjects on LHRH or GnRH agonists may be maintained on these agents)

18. Any serious and/or unstable pre-existing medical, psychiatric, or other conditions that could interfere with subject's safety, provision of informed consent, or compliance to study procedures.

19. Rare hereditary problems of

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non Small Cell Lung Cancer

Intervention

Drug:
• Cabozantinib 20 MG
Cabozantinib will be administered orally at a (starting) dose of 60 mg once daily. The drug is taken continuously over a period of 28 days (4 weeks), which constitutes one treatment cycle. In all subjects, dose reductions (40mg 20mg) and delays to manage toxicity.
• Cabozantinib 40 MG
Cabozantinib will be administered orally at a (starting) dose of 60 mg once daily. The drug is taken continuously over a period of 28 days (4 weeks), which constitutes one treatment cycle. In all subjects, dose reductions (40mg 20mg) and delays to manage toxicity.
• Cabozantinib 60 MG
Cabozantinib will be administered orally at a (starting) dose of 60 mg once daily. The drug is taken continuously over a period of 28 days (4 weeks), which constitutes one treatment cycle. In all subjects, dose reductions and delays to manage toxicity. Cabozantinib should be taken in fasting condition with no food for at least 2 hours before and 1 hour after taking the tablets. A high fat meal significantly increased the median tmax to 6 hours from 4 hours (fasted). The treatment will be continued until disease progression, intolerable toxicity, patient refusal or Investigator's decision or any criterion for withdrawal from the trial or trial drug is fulfilled.

Locations

Country	Name	City	State
Italy	OU di Oncologia Medica- Azienda ospedaliero-Universitaria S. Orsola Malpighi	Bologna
Italy	U.O di Oncologia Medica Policlinico V.Emanuele-G.Rodolico	Catania
Italy	Oncologia Medica 2 -Policlinico San Martino	Genova
Italy	S.S. di Oncologia Medica toraco-polmonare - Fondazione IRCCS - Istituto Nazionale Tumori	Milano
Italy	U.O.C Pneumologia ad Indirizzo Oncologico -AORN Ospedali dei Colli Monaldi-Cotugno-CTO	Napoli
Italy	UOC di Oncologia Medica 2 - IOV Istituto Oncologico Veneto	Padova
Italy	UOC di Oncologia Medica- Azienda Ospidaliero Universitaria di Parma	Parma
Italy	US di Oncologia Medica - A.O. di Perugia	Perugia
Italy	UO Pneumologia - A.O.U Pisana	Pisa
Italy	S.C. di Oncologia Medica - IFO - Istituto Regina Elena	Roma
Italy	UOC di Oncologia Medica - Azienda Sanitaria Universitaria Integrata di Udine	Udine

Sponsors (5)

Lead Sponsor	Collaborator
University of Bologna	AOU S.Orsola Malpighi-Unit of Oncologic Molecular and Transplantations Pathology, Bioikos Ambiente Srl, Ipsen, Mipharm SpA

Country where clinical trial is conducted

Italy, 

References & Publications (21)

Bongarzone I, Vigneri P, Mariani L, Collini P, Pilotti S, Pierotti MA. RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features. Clin Cancer Res. 1998 Jan;4(1):223-8. — View Citation

Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir — View Citation

Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, Hammers HJ, Donskov F, Roth BJ, Peltola K, Lee JL, Heng DYC, Schmidinger M, Agarwal N, Sternberg CN, McDermott DF, Aftab DT, Hessel C, Scheffold C, Schwab G, Hutson TE, Pal S, Motzer RJ — View Citation

Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, Feldman DR, Olencki T, Picus J, Small EJ, Dakhil S, George DJ, Morris MJ. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Po — View Citation

Drilon A, Rekhtman N, Arcila M, Wang L, Ni A, Albano M, Van Voorthuysen M, Somwar R, Smith RS, Montecalvo J, Plodkowski A, Ginsberg MS, Riely GJ, Rudin CM, Ladanyi M, Kris MG. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cance — View Citation

Drilon A, Wang L, Hasanovic A, Suehara Y, Lipson D, Stephens P, Ross J, Miller V, Ginsberg M, Zakowski MF, Kris MG, Ladanyi M, Rizvi N. Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov. 2013 Jun;3(6):630-5. — View Citation

Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010 Dec 15;127(12):2893-917. doi: 10.1002/ijc.25516. — View Citation

Gautschi O, Zander T, Keller FA, Strobel K, Hirschmann A, Aebi S, Diebold J. A patient with lung adenocarcinoma and RET fusion treated with vandetanib. J Thorac Oncol. 2013 May;8(5):e43-4. doi: 10.1097/JTO.0b013e31828a4d07. — View Citation

Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I, Pierotti MA, Della Porta G, Fusco A, Vecchio G. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cel — View Citation

Kodama T, Tsukaguchi T, Satoh Y, Yoshida M, Watanabe Y, Kondoh O, Sakamoto H. Alectinib shows potent antitumor activity against RET-rearranged non-small cell lung cancer. Mol Cancer Ther. 2014 Dec;13(12):2910-8. doi: 10.1158/1535-7163.MCT-14-0274. Epub 20 — View Citation

Kohno T, Ichikawa H, Totoki Y, Yasuda K, Hiramoto M, Nammo T, Sakamoto H, Tsuta K, Furuta K, Shimada Y, Iwakawa R, Ogiwara H, Oike T, Enari M, Schetter AJ, Okayama H, Haugen A, Skaug V, Chiku S, Yamanaka I, Arai Y, Watanabe S, Sekine I, Ogawa S, Harris CC — View Citation

Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, Pfister DG, Cohen EE, Janisch L, Nauling F, Hong DS, Ng CS, Ye L, Gagel RF, Frye J, Müller T, Ratain MJ, Salgia R. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in p — View Citation

Lipson D, Capelletti M, Yelensky R, Otto G, Parker A, Jarosz M, Curran JA, Balasubramanian S, Bloom T, Brennan KW, Donahue A, Downing SR, Frampton GM, Garcia L, Juhn F, Mitchell KC, White E, White J, Zwirko Z, Peretz T, Nechushtan H, Soussan-Gutman L, Kim — View Citation

Masters GA, Temin S, Azzoli CG, Giaccone G, Baker S Jr, Brahmer JR, Ellis PM, Gajra A, Rackear N, Schiller JH, Smith TJ, Strawn JR, Trent D, Johnson DH; American Society of Clinical Oncology Clinical Practice. Systemic Therapy for Stage IV Non-Small-Cell — View Citation

Michels S, Scheel AH, Scheffler M, Schultheis AM, Gautschi O, Aebersold F, Diebold J, Pall G, Rothschild S, Bubendorf L, Hartmann W, Heukamp L, Schildhaus HU, Fassunke J, Ihle MA, Künstlinger H, Heydt C, Fischer R, Nogovà L, Mattonet C, Hein R, Adams A, G — View Citation

Mukhopadhyay S, Pennell NA, Ali SM, Ross JS, Ma PC, Velcheti V. RET-rearranged lung adenocarcinomas with lymphangitic spread, psammoma bodies, and clinical responses to cabozantinib. J Thorac Oncol. 2014 Nov;9(11):1714-9. doi: 10.1097/JTO.0000000000000323 — View Citation

Plaza-Menacho I, Mologni L, McDonald NQ. Mechanisms of RET signaling in cancer: current and future implications for targeted therapy. Cell Signal. 2014 Aug;26(8):1743-52. doi: 10.1016/j.cellsig.2014.03.032. Epub 2014 Apr 3. Review. — View Citation

Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, Asaka R, Hamanaka W, Ninomiya H, Uehara H, Lim Choi Y, Satoh Y, Okumura S, Nakagawa K, Mano H, Ishikawa Y. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012 Feb 12;18(3):378-81. doi: 10.10 — View Citation

Vergote IB, Smith DC, Berger R, Kurzrock R, Vogelzang NJ, Sella A, Wheler J, Lee Y, Foster PG, Weitzman R, Buckanovich RJ. A phase 2 randomised discontinuation trial of cabozantinib in patients with ovarian carcinoma. Eur J Cancer. 2017 Sep;83:229-236. do — View Citation

Wang R, Hu H, Pan Y, Li Y, Ye T, Li C, Luo X, Wang L, Li H, Zhang Y, Li F, Lu Y, Lu Q, Xu J, Garfield D, Shen L, Ji H, Pao W, Sun Y, Chen H. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol. 2 — View Citation

Zbuk KM, Eng C. Cancer phenomics: RET and PTEN as illustrative models. Nat Rev Cancer. 2007 Jan;7(1):35-45. Epub 2006 Dec 14. Review. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	RET aberration	Detection of RET aberration on DNA extracted from circulating tumor cells (CTCs) isolated in blood at baseline (optional)	On the start of treatment (Baseline) and through study completion, an average of 1 year
Other	RET-rearrangment on tumor tissue	Archival tumor tissue (FFPE tumor block or 7-10 unstained slides) will be assessed for determination of RET-rearrangment on tumor cells by using A FISH evaluation of the translocation will be performed using a break-apart probe for the 10p11 locus.	At the start of treatment (baseline)
Primary	Response Rate (RR)	Exact binomial method will be used to estimate the response rate (CR+PR) and its 95% confidence interval.Proportion of patients presenting Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) based on the Investigator's assessment according to standard RECIST criteria v1.1. Patients with no tumor assessment after baseline will be classified as non-responders.	From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
Secondary	Toxicity (frequency of adverse events)	the assessment of safety will be based mainly on the frequency of adverse events; toxicity will be measured according to NCI Common Toxicity Criteria Adverse Event (CTCAE), version 4.03.	From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
Secondary	Progression-Free Survival (PFS)	PFS will be calculated from the first treatment intake to the date of progressive disease, or death.	From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
Secondary	Overall survival (OS)	OS will be calculated from the first treatment intake to death from any cause.	From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
Secondary	Duration of response (DOR	DOR will be calculated from the first treatment intake to the date of disease progression or death.	From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
Secondary	Disease Control Rate(DCR)	DCR will be measured as the sum of complete and partial responses + stable disease.	From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months

External Links

•   An adaptive randomized discontinuation trial of XL184 (BMS-907351) in patients (pts) with advanced solid tumors.
•   Cabozantinib (XL184), a Novel MET and VEGFR2 Inhibitor, Simultaneously Suppresses Metastasis, Angiogenesis, and Tumor Growth