ALEctinib for the Treatment of Pretreated RET-rearranged Advanced Non-small Cell Lung Cancer

Non-small Cell Lung Cancer Clinical Trial

— ALERT-lung  

Official title:

A Single Arm Phase II Trial Evaluating the Activity of Alectinib for the Treatment of Pretreated RET-rearranged Advanced NSCLC

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03445000
• Other study ID #: ETOP 12-17
• Secondary ID: 2017-002063-17MO
• Status: Terminated
• Phase: Phase 2
• Start date: November 6, 2018
• Est. completion date: March 31, 2021

Study information

• Verified date: August 2022
• Source: ETOP IBCSG Partners Foundation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A research study to evaluate the activity of alectinib for the Treatment of pretreated patients with advanced NSCLC that have confirmed RETrearrangement.

Description:

The trial is investigating the efficacy of alectinib in patients with advanced stage RET-rearranged NSCLC, treated with at least one platinum based systemic chemotherapy regimen. Preclinical studies have shown that alectinib, a highly selective next generation ALK inhibitor, has potent anti-tumour activity in RET-rearranged NSCLC. Therapeutically, several multiple kinases inhibitors, are potentially able to inhibit RET kinase function, which has been tested in several unselected NCSLC trials. However, those result were negative and none of the tested drugs was approved for lung cancer treatment. The ALERT-lung trial is a single arm, phase II trial with the primary objective to assess the efficacy of alectinib in terms of best overall response (OR) assessed by RECIST v1.1 in selected NSCLC patients with RET rearrangement. The secondary objectives are to evaluate secondary measures of clinical efficacy including disease control, progression-free survival (PFS), and overall survival (OS) as well as to assess safety and tolerability of the treatment and to describe the association of primary and secondary outcomes with tumour characteristics. Alectinib is administered orally, 600 mg, twice per day, until progression, refusal or unacceptable toxicity. Trial treatment may also continue beyond progression, with physician and patient agreement, for as long as the patient may still derive clinical benefit. A total sample size of 44 patients is required.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 14
• Est. completion date: March 31, 2021
• Est. primary completion date: March 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Histologically or cytologically documented non-small cell lung carcinoma

2. Advanced disease defined as recurrent stage IV (according to 8th TNM classification) or recurrent or progressive disease following multimodal therapy (radiation therapy, surgical resection, or definitive chemo-radiation therapy for locally advanced disease)

3. At least one prior platinum-based systemic regimen: Adjuvant or neoadjuvant or definitive platinum-based chemo-radiotherapy treatments are considered as a line of treatment only if completed less than 6 months before enrolment. Maintenance therapy following platinum doublet-based chemotherapy is not considered a separate regimen of therapy.

4. RET rearrangement detected by FISH, Nanostring or by parallel-sequencing on FFPE tumour tissue assessed locally.

5. Availability of FFPE tumour material for central confirmation of RETrearrangement

6. Measurable or non-measurable, but radiologically evaluable (except for skin lesions) disease according to RECIST v1.1 criteria

7. Age =18 years

8. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

9. Life expectancy >3 months

10. Adequate haematological function:

• Haemoglobin =9 g/dL
• Neutrophil count =1.5 ×109/L
• Platelet count =100 × 109/L
• WBC =2 ×109/L

11. Adequate renal function: Calculated creatinine clearance =45 mL/min (according to Cockcroft-Gault formula)

12. Adequate liver function:

• Total bilirubin =2x ULN (except patients with Gilbert Syndrome, who can have total bilirubin =3.0 mg/dL)
• ALT and AST =3x ULN (=5x ULN for patients with concurrent liver ¨ metastasis)

13. Patient capable of proper therapeutic compliance, and accessible to correct followup.

14. Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine beta HCG pregnancy test within 7 days before enrolment into the trial and within 3 days before alectinib treatment start.

15. Sexually active men and women of childbearing potential must use an effective contraceptive method (intrauterine devices without hormones, bilateral tubal occlusion, vasectomized partner or total abstinence) during the trial treatment and for a period of at least 3 months following the last dose of alectinib.

16. Recovered from any previous therapy related toxicity to Grade =1 at date of enrolment (except for recovery to Grade =2 of alopecia, fatigue, creatinine increased, lack of appetite or peripheral neuropathy)

17. Written Informed Consent (IC) for trial treatment must be signed and dated by the patient and the investigator prior to any trial-related intervention.

Exclusion Criteria:

1. Untreated, active CNS metastases

2. Carcinomatous meningitis

3. Any previous (in the past 3 years) or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ ductal carcinoma of the breast

4. Any serious diseases or clinical conditions, including but not limited to uncontrolled active infection and any other serious underlying medical processes, that could affect the patient's capacity to participate in the trial

5. Liver disease characterized by:

• ALT or AST >3 × ULN (>5 × ULN for patients with concurrent liver metastasis) confirmed on two consecutive measurements or
• Impaired excretory function (e.g., hyperbilirubinaemia) or synthetic function or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, hypoalbuminaemia, ascites, and bleeding from oesophageal varices or
• Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis

6. Patients with baseline symptomatic bradycardia

7. Previous treatment with any RET TKI or RET targeted therapy.

8. Known EGFR, ALK, ROS, and BRAF mutation (in addition to RET rearrangement)

9. Any concurrent systemic anticancer therapy.

10. Any GI disorder that may affect absorption of oral medications, such as malabsorption syndrome or status post major bowel resection.

11. History of hypersensitivity to any of the additives in the alectinib drug formulation.

12. Known HIV positivity or AIDS-related illness.

13. Women who are pregnant or in the period of lactation.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-small Cell Lung Cancer
• Non-small Cell Lung Cancer Metastatic
• Non-small Cell Lung Cancer Recurrent

Intervention

Drug:
• Alectinib
Alectinib is administered orally 600mg (4x150mg capsules), twice per day (8 capsules, total 1200mg daily). The appropriate number of alectinib capsules will be provided to patients to be self-administered at home. Alectinib capsules must be taken at the same time each day with food. If a planned dose of alectinib is missed, patients can take the missed dose up until 6 hours before the next dose.

Locations

Country	Name	City	State
Belgium	Institut Jules Bordet	Brussels
Ireland	St. James Hospital	Dublin
Italy	IRCCS Instituto Tumori Giovanni Paolo II	Bari
Italy	Instituto Europeo di Oncologia (IEO)	Milano
Italy	University Hospital of Turin	Turin
Italy	Universita di Verona	Verona
Netherlands	The Netherlands Cancer Institute Amsterdam	Amsterdam
Netherlands	University Medical Center Maastricht	Maastricht
Spain	Hospital general de Alicante	Alicante
Spain	Hospital Quirón Dexeus	Barcelona
Spain	Hospital Sant Pau	Barcelona
Spain	Vall d'Hebron University Hospital	Barcelona
Spain	Hospital Teresa Herrara	La Coruna
Spain	Hospital Puerta de Hierro	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Regional Universitario Carlos Haya	Málaga
Switzerland	HFR Fribourg	Fribourg
Switzerland	Hôpital Universitaire de Genève	Genève
Switzerland	UniversitatSpital Zurich	Zurich

Sponsors (2)

Lead Sponsor	Collaborator
ETOP IBCSG Partners Foundation	Hoffmann-La Roche

Countries where clinical trial is conducted

Belgium,  Ireland,  Italy,  Netherlands,  Spain,  Switzerland, 

References & Publications (5)

Gainor JF, Shaw AT. Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist. 2013;18(7):865-75. doi: 10.1634/theoncologist.2013-0095. Epub 2013 Jun 28. Review. — View Citation

Gautschi O, Milia J, Filleron T, Wolf J, Carbone DP, Owen D, Camidge R, Narayanan V, Doebele RC, Besse B, Remon-Masip J, Janne PA, Awad MM, Peled N, Byoung CC, Karp DD, Van Den Heuvel M, Wakelee HA, Neal JW, Mok TSK, Yang JCH, Ou SI, Pall G, Froesch P, Za — 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

Lin JJ, Kennedy E, Sequist LV, Brastianos PK, Goodwin KE, Stevens S, Wanat AC, Stober LL, Digumarthy SR, Engelman JA, Shaw AT, Gainor JF. Clinical Activity of Alectinib in Advanced RET-Rearranged Non-Small Cell Lung Cancer. J Thorac Oncol. 2016 Nov;11(11) — 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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Best overall response	Best overall response (OR = CR or PR), per investigator assessment according to RECIST 1.1.	From the start of trial treatment across all time points until the end of trial treatment, assssed up to 44 months.
Secondary	Best overall response per independent review	Best overall response (OR = CR or PR), per independent review assessment according to RECIST 1.1.	From the start of trial treatment across all time points until the end of trial treatment, assssed up to 44 months.
Secondary	Disease control at 24-weeks	Best overall response of CR or PR, or SD (or non-CR/non-PD in the case of non-measurable disease only)	24 weeks after treatment start
Secondary	Progression-free survival (PFS)	PFS will be assessed according to RECIST 1.1 criteria.	From date of enrolment until date of documented progression or death, if progression is not documented, assessed up to 44 months.
Secondary	Overall survival (OS)	Defined as the time from date of enrollment until death from any cause.	From date of enrolment until date of death from any cause, assessed up to 44 months.
Secondary	Safety and tolerability of alectinib treatment	The safety and tolerability of alectinib treatment will be assessed through analysis of the worst grade of toxicity/adverse events according to CTCAE v4.0 criteria observed over the whole treatment period.	Assessed from date of signature of informed consent until 30 days after treatment is ceased for any reason.