Phase 1/2 Study of X-396, an Oral ALK Inhibitor, in Patients With ALK-positive Non-Small Cell Lung Cancer

Non-small Cell Lung Cancer Clinical Trial

Official title:

Phase 1/2, First-in-Human, Dose-Escalation Study of X-396 (Ensartinib) in Patients With Advanced Solid Tumors and Expansion Phase in Patients With ALK-positive Non-Small Cell Lung Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01625234
• Other study ID #: X396-CLI-101
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: June 2012
• Est. completion date: September 17, 2020

Study information

• Verified date: October 2021
• Source: Xcovery Holding Company, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is the first human study to use X-396 (ensartinib), a drug being developed for treatment of advanced cancers. The initial purpose of the study is to determine the largest amount of X-396 that can be safely given to humans (the maximum tolerated dose). Once the recommended Phase 2 dose has been determined, an expansion phase will assess the preliminary anti-tumor activity of X-396 in ALK-positive non-small cell lung cancer. The study will also provide early information on how the body handles the drug (pharmacokinetics) and on the efficacy of X-396.

Description:

This is the first study of X-396 (ensartinib) in humans and the investigational drug will be given as a once or twice daily oral dose in 28 day cycles until there is disease progression or unacceptable safety issues. X-396 will be given to small groups of patients (1 - 6) at each dose level and the patients will be observed to see if there are any adverse safety effects. As long as there are no unacceptable safety issues after 28 days, the dose of X-396 will be increased for the next group of patients. This process will continue until the maximum tolerated dose (MTD) of X-396 is reached. Once the MTD is reached, up to 170 additional patients will also be given X-396 to further determine the activity of X-396 in patients with ALK-positive non-small cell lung cancer. These additional patients will be enrolled in the following expansion cohorts: ALK TKI-naïve patients, patients that progressed on crizotinib, patients that progressed on one or more 2nd generation ALK TKIs (patients may or may not have also received prior crizotinib), including patients with asymptomatic CNS metastases.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 131
• Est. completion date: September 17, 2020
• Est. primary completion date: September 17, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of advanced solid tumor malignancy. Patients may be ALK TKI-naive or may have received prior crizotinib and/or second generation ALK TKIs. In addition, patients with a known ALK 1198 mutation will be allowed.

-For the expanded cohort portion of the study, patients must have NSCLC with ALK genomic alterations; however, patients will be allowed to enroll based on local FDA-approved ALK results.

2. Eastern Cooperative Group ECOG) Performance Status score of 0 or 1.

3. Ability to swallow and retain oral medication.

4. Adequate organ system function.

5. Patients with treated or untreated asymptomatic CNS metastases may be allowed to enroll.

6. Male patients willing to use adequate contraceptive measures.

7. Female patients who are not of child-bearing potential, and female patients of child-bearing potential who agree to use adequate contraceptive measures.

8. Patients must be = 18 years of age.

9. Patients must have measurable or evaluable disease for the dose escalation portion of the study and measurable disease for the expanded cohort portion of the study (except for patients in the CNS metastases and leptomeningeal cohorts).

10. Willingness and ability to comply with the trial and follow-up procedures.

11. Ability to understand the nature of this trial and give written informed consent.

Exclusion Criteria:

1. Patients currently receiving cancer therapy.

2. Use of an investigational drug within 21 days or 5 half-lives (whichever is shorter) prior to the first dose of X-396. A minimum of 10 days between treatment and X-396 and 2 days between ALK TKI and X-396.

3. Any major surgery, radiotherapy, or immunotherapy within the last 21 days (focal radiation does not require a washout period; =4 weeks for WBRT). Chemotherapy regimens with delayed toxicity within the last 4 weeks. Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last 2 weeks.

4. Prior stem cell transplant.

5. Patients with a known allergy or delayed hypersensitivity reaction to drugs chemically related to X-396 (e.g., crizotinib) or to the active ingredient of X-396.

6. Patients with primary CNS tumors are ineligible.

7. Patients receiving CYP3A substrates with narrow therapeutic indices, strong CYP3A inhibitors, and strong CYP3A inducers.

8. Concomitant use of herbal medications at least 7 days prior to the first dose of study drug and throughout participation in the trial.

9. Females who are pregnant or breastfeeding.

10. Presence of active gastrointestinal (GI) disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of X-396.

11. Clinically significant cardiovascular disease.

12. Patients who are immunosuppressed (including known HIV infection), have a serious active infection at the time of treatment, have known hepatitis C, or have any serious underlying medical condition that would impair the ability of the patient to receive protocol treatment.

13. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.

14. Concurrent condition that in the investigator's opinion would jeopardize compliance with the protocol or would impart excessive risk associated with study participation that would make it inappropriate for the patient to be enrolled.

15. Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol.

Related Conditions & MeSH terms

• Advanced Solid Tumors
• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-small Cell Lung Cancer

Intervention

Drug:
• Phase I: X-396 (ensartinib)
Oral, ALK inhibitor
• Phase II: X-396 (ensartinib)
Expanded Cohort

Locations

Country	Name	City	State
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	City of Hope National Med Ctr	Duarte	California
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	UCSD Moores Cancer Center	La Jolla	California
United States	University of Southern California Norris Comprehensive Cancer Center	Los Angeles	California
United States	University of Wisconsin Carbone Cancer Ctr	Madison	Wisconsin
United States	Tennessee Oncology, PLLC	Nashville	Tennessee
United States	Vanderbilt University	Nashville	Tennessee
United States	New York University Langone Medical Center	New York	New York
United States	Providence Portland Medical Center	Portland	Oregon
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Stanford University	Stanford	California
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Xcovery Holding Company, LLC

Country where clinical trial is conducted

United States, 

References & Publications (2)

Horn L, Infante JR, Reckamp KL, Blumenschein GR, Leal TA, Waqar SN, Gitlitz BJ, Sanborn RE, Whisenant JG, Du L, Neal JW, Gockerman JP, Dukart G, Harrow K, Liang C, Gibbons JJ, Holzhausen A, Lovly CM, Wakelee HA. Ensartinib (X-396) in ALK-Positive Non-Smal — View Citation

Lovly CM, Heuckmann JM, de Stanchina E, Chen H, Thomas RK, Liang C, Pao W. Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors. Cancer Res. 2011 Jul 15;71(14):4920-31. doi: 10.1158/0008-5472.CAN-10-3879. Epub 2011 May 25. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Tolerated Dose	To evaluate the safety/tolerability of X-396 (ensartinib) and determine the maximum tolerated dose (MTD) of X-396 as a single agent.	12 months
Secondary	Plasma Concentrations (Cmax, Tmax, AUC, half-life)	To characterize the preliminary pharmacokinetics including Cmax, Tmax, AUC, half-life of X-396 given as a single agent	18 months
Secondary	Preliminary Tumor Response	To explore the preliminary clinical tumor response after treatment with X-396 (ensartinib) given as a single agent.	18 months