Clinical trial NCT03445000: ALEctinib for the Treatment of Pretreated RET-rearranged Advanced Non-small Cell Lung Cancer
Official title: A Single Arm Phase II Trial Evaluating the Activity of Alectinib for the Treatment of Pretreated RET-rearranged Advanced NSCLC
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer
Non-small Cell Lung Cancer Metastatic
Non-small Cell Lung Cancer Recurrent
Keywords: RET-rearrangement
advanced NSCLC
Lead sponsor: ETOP IBCSG Partners Foundation
Sponsor class: NETWORK
Collaborators: name: Hoffmann-La Roche
First posted: 2018-02-26
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Best Overall Response (BOR)
timeFrame: Evaluated from enrollment through study completion, up to a maximum of 28 months.
Secondary outcomes:
measure: Disease Control at 24-weeks
timeFrame: From first documented response (CR, PR, SD, non-CR/non-PD) to 24 weeks or first documented progression or death from any cause, whichever came first, assessed every 8 weeks (±4 days).
measure: Progression-free Survival (PFS)
timeFrame: Evaluated from enrollment through study completion, up to a maximum of 28 months.
measure: Overall Survival (OS)
timeFrame: Evaluated from enrollment through study completion, up to a maximum of 28 months.
measure: Number of Patients Experienced Adverse Events
timeFrame: Evaluated from enrollment through study completion, up to a maximum of 28 months.
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Dublin
country: Ireland
facility: St. James Hospital
city: Bari
country: Italy
facility: IRCCS Instituto Tumori Giovanni Paolo II
city: Milano
country: Italy
facility: Instituto Europeo di Oncologia (IEO)
city: Turin
country: Italy
facility: University Hospital of Turin
city: Verona
country: Italy
facility: Universita di Verona
city: Amsterdam
country: Netherlands
facility: The Netherlands Cancer Institute Amsterdam
city: Maastricht
country: Netherlands
facility: University Medical Center Maastricht
city: Alicante
country: Spain
facility: Hospital general de Alicante
city: Barcelona
country: Spain
facility: Vall d'Hebron University Hospital
city: Barcelona
country: Spain
facility: Hospital Quirón Dexeus
city: Barcelona
country: Spain
facility: Hospital Sant Pau
city: La Coruna
country: Spain
facility: Hospital Teresa Herrara
city: Madrid
country: Spain
facility: Hospital Puerta de Hierro
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Málaga
country: Spain
facility: Hospital Regional Universitario Carlos Haya
city: Fribourg
country: Switzerland
facility: HFR Fribourg
city: Genève
country: Switzerland
facility: Hôpital Universitaire de Genève
city: Zurich
country: Switzerland
facility: UniversitatSpital Zurich
Study officials:
affiliation: Vall d'Hebron University Hospital
name: Enriqueta Felip, MD-PhD
role: STUDY_CHAIR
affiliation: University Hospital Cologne
name: Jürgen Wolf, MD-PhD
role: STUDY_CHAIR
affiliation: The Netherlands Cancer Institute Amsterdam
name: Egbert F. Smith, MD-PhD
role: STUDY_CHAIR
References:
citation: 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.
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: 10.1038/nm.2658.
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):2027-2032. doi: 10.1016/j.jtho.2016.08.126. Epub 2016 Aug 17.
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, Zalcman G, Gandara DR, Riess JW, Velcheti V, Zeidler K, Diebold J, Fruh M, Michels S, Monnet I, Popat S, Rosell R, Karachaliou N, Rothschild SI, Shih JY, Warth A, Muley T, Cabillic F, Mazieres J, Drilon A. Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry. J Clin Oncol. 2017 May 1;35(13):1403-1410. doi: 10.1200/JCO.2016.70.9352. Epub 2017 Mar 13.
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 2014 Oct 27.