Phase 1/2 Study of Ensartinib and Durvalumab, in ALK-rearranged Non-small Cell Lung Cancer

NCT02898116 | Completed Phase 1 Results FDA Drug

• 1 other identifier: LUD2014-012-ALK
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

This was a Phase 1/2, open-label, multicenter, single-arm study of combination therapy with ensartinib, an anaplastic lymphoma kinase (ALK) inhibitor, and durvalumab, an anti-programmed cell death ligand 1 (PD-L1) antibody, in subjects with ALK-rearranged (ALK-positive) non-small cell lung cancer (NSCLC). Primary study objectives were to determine the recommended combination dose (RCD) and safety and tolerability of the combination. Further objectives were to evaluate the clinical efficacy and biologic activity of the combination.

Conditions

Non-small Cell Lung Cancer; Carcinoma; NSCLC

Keywords

ALK-rearranged; ALK-positive; ALK Inhibitor; Ensartinib; X-396; anti-PD-L1; Durvalumab; MEDI4736; ALK

Outcome Measures

Primary Outcomes (1)

• Number of Subjects With Treatment-emergent Adverse Events

  Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Treatment-emergent adverse events (TEAEs) were reported based on clinical laboratory tests, physical examinations, and vital signs from pre-treatment through the end of the study period. Dose-limiting toxicity (DLT) during the Run-in Period was defined as ≥ Grade 2 rash or other toxicity requiring discontinuation of ensartinib dosing.

  up to 3 months

Secondary Outcomes (2)

• Number of Subjects With Best Overall Tumor Response at the Last Assessment

  up to 3 months

• Number of Subjects With Immune-related Tumor Response at the Last Assessment

  up to 3 months

Study Arms (1)

Ensartinib ± Durvalumab

EXPERIMENTAL

Subjects were to receive ensartinib monotherapy during a pre-immunotherapy Run-in Period for one to two 28-day cycles, followed by combination therapy with ensartinib plus durvalumab for subjects with no DLTs during the Run-in Period.

Drug: Ensartinib; Drug: Durvalumab

Interventions

Ensartinib DRUG

Ensartinib was administered orally once daily at a dose of 200 mg during the Run-in Period. During combination therapy, the ensartinib starting dose was to be 200 mg. Based on observed toxicity at the starting dose level, the ensartinib dose may have been escalated to the recommended single-agent dose (225 mg) or de-escalated to the minimum effective dose (150 mg).

Also known as: X-396

Ensartinib ± Durvalumab

Durvalumab DRUG

During combination therapy, durvalumab was to be administered as an IV infusion over 60 (± 5) minutes every 4 weeks at a dose of 1500 mg.

Also known as: MEDI4736

Ensartinib ± Durvalumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologic confirmation of metastatic NSCLC. Subjects must have had confirmed ALK rearrangement as assessed by immunohistochemistry. Subjects may have had prior therapy with ALK inhibitors (other than ensartinib) or been ALK inhibitor naïve. ALK inhibitor naïve subjects were informed of the availability of approved ALK inhibitors.
• Measurable disease according to RECIST 1.1, defined as ≥ 1 lesion that could be accurately measured in ≥ 1 dimension (longest diameter to be recorded for non-lymph node lesions, shortest diameter to be recorded for lymph node lesions). Each lesion must have been ≥ 10 mm when measured by computed tomography, magnetic resonance imaging, or caliper measurement by clinical examination or ≥ 20 mm when measured by chest x-ray.
• Willing to provide a fresh pre-treatment biopsy; however, if subject was ALK inhibitor naïve, either archival or pre-treatment biopsy was acceptable.
• Asymptomatic subjects with surgically treated brain metastases must have been ≥ 14 days post surgery at the time of first dosing, while clinically stable with no requirement for steroids. Asymptomatic subjects with radiation-treated brain metastases may have entered the study immediately after completion of the radiation (and been off steroids, if applicable). Symptomatic subjects (those experiencing headache, seizure etc.), must have been relieved from all symptoms of their central nervous system disease, and must have completed radiation and been off steroids prior to first dosing (anti seizure medicine permitted).
• Laboratory parameters for vital functions should have been in the normal range. Laboratory abnormalities that were not clinically significant were generally permitted, except for the following laboratory parameters, which must have been within the ranges specified, regardless of clinical significance:
• Hemoglobin: ≥ 9 g/dL
• Neutrophil count: ≥ 1.5 x 10\^9/L
• Platelet count: ≥ 100,000/mm\^3
• Serum creatinine: ≤ 1.5 x institutional upper limit of normal (ULN), OR creatinine clearance: ≥ 50 mL/min (by Cockcroft-Gault formula)
• Serum total bilirubin: ≤ 1.5 × ULN (except for subjects with Gilbert's syndrome who were allowed after consultation with their physician)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT): ≤ 2.5 x ULN
• Alkaline phosphatase: ≤ 2.5 x ULN
• Eastern Cooperative Oncology Group Performance Status ≤ 2.
• Age ≥ 18 years.
• Able and willing to provide valid written informed consent.

You may not qualify if:

• Treatment with an investigational agent within 4 weeks of starting treatment, and any prior drug-related toxicity (except alopecia) should have recovered to Grade 1 or less.
• Prior treatment with anti-PD-1, PD-L1 (including durvalumab), or cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), or ensartinib (X-396).
• Active, suspected or prior documented autoimmune disease (including but not restricted to inflammatory bowel disease, celiac disease, Wegner's granulomatosis, Hashimoto's thyroiditis, rheumatoid arthritis, systemic lupus, scleroderma and its variants, multiple sclerosis, myasthenia gravis). Vitiligo, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger were permitted.
• Subjects with clinically significant cardiovascular disease, including:
• New York Heart Association Class II or higher congestive heart failure.
• Myocardial infarction, unstable angina, cerebrovascular accident or transient ischemic attack within 6 months of start of study drug (Day -28).
• Clinically significant supraventricular or ventricular arrhythmia.
• QT interval corrected using Fridericia's formula (QTcF) ≥ 450 ms (male) or QTcF ≥ 470 ms (female).
• Clinically uncontrolled hypertension.
• History of pneumonitis or interstitial lung disease, or any unresolved immune-related adverse events following prior therapy.
• Major surgery within 4 weeks of starting treatment (or scheduled for surgery during the projected course of the study).
• Women of child bearing potential who were pregnant as evidenced by positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) or nursing.
• Female subjects of childbearing potential who were sexually active with a non-sterilized male partner must have used at least one highly effective method of contraception (see table below) from the time of screening and must have agreed to continue using such precautions for 90 days after the final dose of investigational products. Non-sterilized male partners of a female subject must have used male condoms plus spermicide throughout this period. Cessation of birth control after this point should have been discussed with a responsible physician. Not engaging in sexual activity for the total duration of the trial and the drug washout period was an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method were not acceptable methods of birth control.
• Female subjects should have refrained from breastfeeding throughout the period described above.
• Females of childbearing potential were defined as those who were not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.

Sponsors & Collaborators

• Ludwig Institute for Cancer Research: lead
• MedImmune LLC: collaborator
• Xcovery Holdings, Inc.: collaborator
• Cancer Research Institute, New York City: collaborator

Study Sites (1)

Research Facility

New York, New York, 10016, United States

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Carcinoma

Interventions

ensartinib; durvalumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Limitations and Caveats

Early termination due to the rapidly changing treatment landscape for ALK-positive NSCLC, resulting in low enrollment. Because only 2 subjects were enrolled, no separate statistical analysis plan was issued and no formal data analyses were performed.

Results Point of Contact

• Title: Jonathan Skipper PhD
• Organization: Ludwig Institute for Cancer Research

jskipper@lcr.org

12124501539

Study Officials

• Leena Gandhi, MD, PhD

  Laura & Isaac Perlmutter Cancer Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 8, 2016
• First Posted: September 13, 2016
• Study Start: May 10, 2017
• Primary Completion: August 4, 2017
• Study Completion: August 4, 2017
• Last Updated: October 10, 2022
• Results First Posted: August 21, 2018

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)