Clinical trial NCT03318939: Phase 2 Study of Poziotinib in Participants With NSCLC Having EGFR or HER2 Exon 20 Insertion Mutation
Official title: A Phase 2 Study of Poziotinib in Patients With Non-Small Cell Lung Cancer (NSCLC), Locally Advanced or Metastatic, With EGFR or HER2 Exon 20 Insertion Mutation (ZENITH20)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: NSCLC
Keywords: EGFR
HER2
Exon 20 insertion mutation
Lead sponsor: Spectrum Pharmaceuticals, Inc
Sponsor class: INDUSTRY
First posted: 2017-10-24
Enrollment: 648
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Each treatment cycle is 28 calendar days in duration. There will be seven participant cohorts and eligible participants will be enrolled into each cohort in parallel based on EGFR or HER2 exon 20 mutation status and prior treatment status:

* Cohort 1: Previously treated participants with EGFR exon 20 insertion mutant positive NSCLC (closed to enrollment)
* Cohort 2: Previously treated participants with HER2 exon 20 insertion mutant positive NSCLC (closed to enrollment)
* Cohort 3: Treatment naïve participants with EGFR exon 20 insertion mutant positive NSCLC (fully enrolled)
* Cohort 4: Treatment naïve participants with HER2 exon 20 insertion mutant positive NSCLC
* Cohort 5: Participants who meet the criteria for enrollment in Cohort 1 to 4, but the enrollment in the respective cohort has been closed
* Cohort 6: Participants with acquired EGFR mutation who progressed while on treatment with first-line osimertinib
* Cohort 7: Participants with EGFR or HER2 activating mutations
Primary purpose: TREATMENT

Brief summary: This is a Phase 2, open-label, multi-center study to evaluate the efficacy and the safety/tolerability of poziotinib in seven participant cohorts for up to 603 previously treated and treatment-naïve NSCLC participant. Cohorts 3 and 4 were added with Amendment 1 and three additional cohorts were added with Amendment 2 (Cohorts 5, 6 and 7).

Detailed description: The Screening period (Day -30 to Day -1) lasts up to approximately 30 days prior to Cycle 1, Day 1. Participant must meet all Inclusion/Exclusion Criteria to participate in the study. Eligible participants will provide written Informed Consent prior to undergoing any study procedures.

Each treatment cycle is 28 calendar days in duration. There will be seven participant cohorts and eligible participants will be enrolled into each cohort in parallel based on EGFR or HER2 exon 20 mutation status and prior treatment status:

* Cohort 1: Previously treated participant with EGFR exon 20 insertion mutation positive NSCLC (complete)
* Cohort 2: Previously treated participant with HER2 exon 20 insertion mutation positive NSCLC (complete)
* Cohort 3: Treatment naïve participant with EGFR exon 20 insertion mutation positive NSCLC (complete)
* Cohort 4: Treatment naïve participant with HER2 exon 20 insertion mutation positive NSCLC (fully enrolled)
* Cohort 5: Participants who meet the criteria for enrollment in Cohort 1 to 4, but the enrollment in the respective cohort has been closed (closed to enrollment)
* Cohort 6: Participants with acquired EGFR mutation who progressed while on treatment with first-line osimertinib (closed to enrollment)
* Cohort 7: Participants with EGFR or HER2 activating mutations (closed to enrollment)

Toxicity will be assessed based on the grade of the adverse events using CTCAE version 4.03.

On Day 1 of each 28-day cycle, the participant's absolute neutrophil count (ANC) must be ≥1.5×10\^9/L and platelet count must be ≥100×10\^9/L before administering poziotinib. All participants will be treated until disease progression (except for first progression in Cohort 5), death, intolerable adverse events (AEs), or other protocol-specified reasons for participant withdrawal.

Eligibility criteria: Key Inclusion Criteria:

* Participant must be willing and capable of giving written Informed Consent, adhering to dosing and visit schedules, and meeting all study requirements
* Participant has histologically or cytologically confirmed locally advanced or metastatic non-small cell lung cancer (NSCLC) that is not amenable to treatment with curative intent
* Prior treatment status:

  * Cohorts 1 and 2: Participant has had at least one prior systemic treatment for locally advanced or metastatic NSCLC
  * Cohorts 3 and 4: Participant is treatment-naïve for locally advanced or metastatic NSCLC and eligible to receive first-line treatment with poziotinib as determined by the Investigator. Adjuvant/neo-adjuvant therapies (chemotherapy, radiotherapy, or investigational agents) are permissible as long as they end at least 15 days prior to study entry.
  * Cohort 5: Participants who meet the criteria for enrollment in Cohorts 1 to 4, but the enrollment in the respective cohort has been closed
  * Cohort 6: Participant with EGFR mutation-positive NSCLC who progressed while on treatment with first-line osimertinib
  * Cohort 7: Participant has had at least one prior systemic treatment for locally advanced or metastatic NSCLC
* Specific mutations:

  * Cohort 1 and 3: Documented EGFR exon 20 insertion mutation
  * Cohort 2 and 4: Documented HER2 exon 20 insertion mutation
  * Cohort 5: Documented EGFR or HER2 exon 20 insertion mutations
  * Cohort 6: Documented acquired EGFR mutation (tested after osimertinib progression)
  * Cohort 7: Documented EGFR or HER2 activating mutations
* Participant has adequate organ function at Baseline

Key Exclusion Criteria:

* Participant has had previous treatment with poziotinib or any other EGFR or HER2 exon 20 insertion mutation-selective tyrosine kinase inhibitor (TKI) prior to study participation. The currently approved TKIs (ie, erlotinib, gefitinib, afatinib, osimertinib) are not considered to be exon 20 insertion-selective and are permissible (Cohorts 1 and 2).
* Participant is concurrently receiving chemotherapy, biologics, immunotherapy for cancer treatment; systemic anti-cancer treatment or investigational treatment should not be used within 2 weeks or 5 half lives, whichever is longer; local radiation therapy for bone pain may be allowed
* Participant has had other malignancies within the past 3 years, except for stable non-melanoma skin cancer, fully-treated and stable, early-stage prostate cancer, or carcinoma in situ of the cervix or breast without need of treatment
* Participant is pregnant or breast-feeding

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: 24 months
Secondary outcomes:
measure: Disease Control Rate (DCR)
timeFrame: 24 months
measure: Duration of Response (DoR)
timeFrame: 24 months
Other outcomes:
measure: Progression-free Survival (PFS) - Exploratory
timeFrame: 24 months
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: Arcadia
country: United States
facility: Oncology Physician's Network Inc./OPN Healthcare
state: California
city: Duarte
country: United States
facility: City of Hope
state: California
city: La Jolla
country: United States
facility: UCSD -Moores Cancer Center
state: California
city: Long Beach
country: United States
facility: Pacific Shores Medical Group
state: California
city: Los Angeles
country: United States
facility: Los Angeles Hematology Oncology Medical Group
state: California
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center
state: California
city: Sacramento
country: United States
facility: UC Davis Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: UCSF Helen Diller Comprehensive Cancer Center at Mt Zion
state: California
city: Santa Monica
country: United States
facility: UCLA Hematology/Oncology
state: California
city: Torrance
country: United States
facility: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
state: California
city: Vallejo
country: United States
facility: Kaiser Permanente Medical Center
state: California
city: Boulder
country: United States
facility: Rocky Mountain Cancer Center
state: Colorado
city: New Haven
country: United States
facility: Yale University, Yale Cancer Center Smilow Cancer Hospital at Yale
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Orlando
country: United States
facility: Florida Hospital
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center & Research Institute
state: Florida
city: Winter Haven
country: United States
facility: The Bond & Steele Clinic, P.A. dba Bond Clinic, P.A.
state: Florida
city: Athens
country: United States
facility: University Cancer & Blood Center, LLC
state: Georgia
city: Newnan
country: United States
facility: CTCA - Southeastern Regional Medical Center
state: Georgia
city: Zion
country: United States
facility: CTCA - Midwestern Regional Medical Center
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Minneapolis
country: United States
facility: Minnesota Oncology Hematology, P.A.
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Hattiesburg
country: United States
facility: Hattiesburg Clinic Hematology/Oncology
state: Mississippi
city: Bronx
country: United States
facility: Montefiore Einstein Medical Center for Cancer Care
state: New York
city: Bronx
country: United States
facility: North Shore Hematology Oncology Associates DBA New York Cancer and Blood Specialists
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Port Jefferson Station
country: United States
facility: North Shore Hematology Oncology Associates P.C. DBA NY Cancer and Blood Specialists
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Tulsa
country: United States
facility: Oklahoma Cancer Specialists and Research Institute, LLC
state: Oklahoma
city: Philadelphia
country: United States
facility: CTCA - Eastern Regional Medical Center
state: Pennsylvania
city: Memphis
country: United States
facility: Baptist Cancer Center
state: Tennessee
city: Austin
country: United States
facility: Texas Oncology- Austin
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Brussels
country: Belgium
facility: Saint Luc University Hospital
city: Leuven
country: Belgium
facility: University Hospitals Leuven
city: Mons
country: Belgium
facility: Ambroise Pare University Hospital Center
city: Roeselare
country: Belgium
facility: General Hospital Delta
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Vancouver
country: Canada
facility: BC Cancer - Vancouver
state: British Columbia
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Toulouse
country: France
facility: Hopital Larrey, CHU Toulouse, Unité d'Oncologie des Voies Respiratoires
city: Villejuif
country: France
facility: Gustave Roussy Oncology Institute, Department of Medical Oncology
city: Be'er Sheva
country: Israel
facility: Soroka Medical Center
city: Haifa
country: Israel
facility: Rambam Healthcare Campus
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Petah Tikva
country: Israel
facility: Rabin Medical Center
city: Milan
country: Italy
facility: National Cancer Institute, IRCCS, Department of Medical Oncology
city: Ravenna
country: Italy
facility: Santa Maria delle Croci Hospital
city: Rome
country: Italy
facility: National Cancer Institute Regina Elena, IRCCS, Operative Unit of Medical Oncology A 1
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: Barcelona
country: Spain
facility: University Hospital Germans Trias i Pujol, Department of Medical Oncology
city: Madrid
country: Spain
facility: University Hospital 12 de Octubre
Study officials:
References:
citation: Le X, Cornelissen R, Garassino M, Clarke JM, Tchekmedyian N, Goldman JW, Leu SY, Bhat G, Lebel F, Heymach JV, Socinski MA. Poziotinib in Non-Small-Cell Lung Cancer Harboring HER2 Exon 20 Insertion Mutations After Prior Therapies: ZENITH20-2 Trial. J Clin Oncol. 2022 Mar 1;40(7):710-718. doi: 10.1200/JCO.21.01323. Epub 2021 Nov 29.