A Study of TAK-788 in Adults With Non-Small Cell Lung Cancer

Carcinoma, Non-Small-Cell Lung Clinical Trial

Official title:

A Phase 1/2 Study of the Safety, Pharmacokinetics, and Anti-Tumor Activity of the Oral EGFR/HER2 Inhibitor TAK-788 (AP32788) in Non-Small Cell Lung Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02716116
• Other study ID #: AP32788-15-101
• Secondary ID: U1111-1217-72052
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: June 16, 2016
• Est. completion date: March 28, 2025

Study information

• Verified date: October 2023
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is about a medicine called TAK-788, also known as mobocertinib, given to adults with non-small cell lung cancer. The main aims of this study are to check if there are any side effects from TAK-788, to learn how TAK-788 is processed by the body, and to determine the best dose of TAK-788 to treat this condition. Participants will take TAK-788 capsules with chemotherapy. Participants will continue to take TAK-788 unless they or their doctor decide they should stop this treatment. Participants will take TAK-788 capsules with or without chemotherapy under antidiarrhea prevention to determine the safety of TAK-788 treatment. Non-Asian, non-White participants will take TAK-788 to determine the safety and tolerability of TAK-788 treatment.

Description:

This phase 1/2 study will evaluate the safety, pharmacokinetics, and anti-tumor activity of oral EGFR/HER2 Inhibitor TAK-788 in participants with NSCLC and anti-tumor activity of TAK-788 in participants with solid tumors other than NSCLC with EGFR or HER2 mutations. The trial will be conducted in three parts: a dose escalation (Part 1), expansion phase (Part 2), followed by an extension phase (Part 3).

The objectives of the dose escalation phase (Part 1), is to determine the safety profile of orally administered TAK-788, including the MTD, DLTs, RP2D, pharmacokinetic profile. The primary goal of the expansion component of the trial is to evaluate the anti-tumor activity of TAK-788 in seven histologically and molecularly defined cohorts at the RP2D (determined based on dose escalation phase of the trial).

The seven expansion cohorts will be:

1. NSCLC participants with EGFR exon 20 activating insertions, who have either not received or not shown an objective response to an EGFR TKI, and who have no active, measurable CNS metastases;

2. NSCLC participants with HER2 exon 20 activating insertions or point mutations and no active, measurable CNS metastases;

3. NSCLC participants with EGFR exon 20 activating insertions or HER2 exon 20 activating insertions or point mutations and active, measurable CNS metastases;

4. NSCLC participants with other targets against which TAK-788 is active (examples include EGFR exon 19 deletions or exon 21 substitutions [with or without T790M mutations] and other uncommon EGFR activating mutations), without active CNS metastases;

5. NSCLC participants with EGFR exon 20 activating insertions, who have previously shown an objective response to an EGFR TKI and subsequently progressed, without active CNS metastases;

6. NSCLC participants with EGFR exon 20 activating insertions, who have not received prior systemic anticancer treatment for locally advanced or metastatic disease, without active CNS metastases; and

7. Participants with solid tumors other than NSCLC with EGFR/HER2 mutations against which TAK-788 is active, without active CNS metastases.

The extension phase will evaluate efficacy of TAK-788 in participants with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations and who have been previously treated. The study enrolled 324 participants.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 334
• Est. completion date: March 28, 2025
• Est. primary completion date: March 28, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

General Inclusion Criteria all cohorts: dose escalation, antidiarrhea prophylaxis, dose escalation combination, expansion, and extension:

1. Have histologically or cytologically confirmed locally advanced (and not a candidate for definitive therapy) or metastatic NSCLC disease (Stage IIIB or IV) or other solid tumors. For all cohorts except Expansion Cohort 7, the locally advanced or metastatic disease is NSCLC. For Expansion Cohort 7, the locally advanced or metastatic disease is any solid tumor other than NSCLC.

2. Must have sufficient tumor tissue available for analysis.

3. Must have measurable disease by response evaluation criteria in solid tumors (RECIST) v1.1.

4. Male or female adult participants (aged 18 years or older, or as defined per local regulations).

5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.

6. Minimum life expectancy of 3 months or more.

7. Adequate organ function at baseline.

8. Normal QT interval on screening electrocardiogram (ECG), defined as QT interval corrected (Fridericia) (QTcF) of less than or equal to (= ) 450 millisecond (ms) in males or = 470 ms in females.

9. Willingness and ability to comply with scheduled visits and study procedures.

Part 1: Dose Escalation Cohort Specific Inclusion Criteria:

1. Refractory to standard available therapies.

Part 2: Expansion Cohort 1 Specific Inclusion Criteria:

1. Have a documented EGFR in-frame exon 20 insertion by a local test.

2. Previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease.

3. Prior treatment with an EGFR TKI is allowed unless the participants had an objective response and subsequent progression as assessed by the investigator or treating physician.

Expansion Cohort 2 Specific Inclusion Criteria:

1. Have one of the following documented by a local test:

1. A HER2 exon 20 insertion;

2. An activating point mutation in HER2.

2. Previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease.

3. With an EGFR exon 20 insertion: Prior treatment with a pan-HER TKI (example, afatinib, neratinib, or dacomitinib) is allowed unless the participants had an objective response and subsequent progression as assessed by the investigator or treating physician.

Part 2: Expansion Cohort 3 Specific Inclusion Criteria:

1. Have one of the following documented by a local test:

1. An EGFR exon 20 insertion;

2. A HER2 exon 20 insertion;

3. An activating point mutation in HER2.

2. Previously treated with one or more regimen of systemic therapy for locally advanced or metastatic disease.

3. For participants with an EGFR exon 20 insertion: prior treatment with an EGFR TKI is allowed unless the participants had an objective response and subsequent progression as assessed by the investigator or treating physician.

4. For participants with a HER2 exon 20 insertion or HER2 activating point mutation:

prior treatment with a pan-HER TKI (example, afatinib, neratinib, or dacomitinib) is allowed unless the participants had an objective response and subsequent progression as assessed by the investigator or treating physician during treatment with that prior TKI.

5. Have either previously untreated intracranial CNS metastases or previously treated intracranial CNS metastases with radiologically documented new or progressing CNS lesions.

6. Have at least one target (that is, measurable) intracranial CNS lesion (greater than or equal to [ = ]10 millimeter [mm] in longest diameter by contrast enhanced magnetic resonance imaging [MRI]).

Part 2: Expansion Cohort 4 Specific Inclusion Criteria:

1. Have one of the following documented by a local test: an activating mutation in EGFR including exon 19 deletions or exon 21 L858R substitution (with or without T790M), or an uncommon activating mutation other than exon 20 insertion including, but not limited to, G719X (where X is any other amino acid), S768I, L861Q, or L861R.

2. Treatment naive for locally advanced or metastatic disease or previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease.

Part 2: Expansion Cohort 5 Specific Inclusion Criteria:

NSCLC participants with EGFR exon 20 activating insertions, who have previously shown an objective response to an EGFR TKI and subsequently progressed, without active CNS metastases.

1. Have a documented EGFR in-frame exon 20 insertion by a local test.

2. Previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease.

3. Previously showed an objective response to an EGFR TKI, and subsequently progressed as assessed by the investigator or treating physician.

Part 2: Expansion Cohort 6 Specific Inclusion Criteria:

NSCLC participants with EGFR exon 20 activating insertions, who have not received prior systemic anticancer treatment for locally advanced or metastatic disease, without active CNS metastases.

1. Have a documented EGFR in-frame exon 20 insertion by a local test.

2. No prior systemic treatment for locally advanced or metastatic disease.

Part 2: Expansion Cohort 7 Specific Inclusion Criteria:

Participants with solid tumors other than NSCLC with EGFR/HER2 mutations against which TAK-788 is active, without active CNS metastases.

1. Have a solid tumor that is not NSCLC, including, but not limited to, bladder/urinary tract cancer, breast cancer, gastric/esophageal cancer, biliary tract cancer, and head and neck cancer.

2. Is refractory to standard therapy.

3. Have EGFR or HER2 mutations, documented by a local test.

Part 3: Extension Cohort Specific Inclusion Criteria:

1. Have a documented EGFR in-frame exon 20 insertion by a local test and sufficient tumor tissue available for central analysis.

2. Must have received at least 1 prior line of therapy for locally advanced or metastatic disease and no more than 2 regimens of systemic anticancer chemotherapies for locally advanced or metastatic disease.

• Prior treatment with an EGFR TKI is allowed unless the participant had an objective response and subsequent progression as assessed by the investigator or treating physician during treatment with that prior TKI.

Exclusion Criteria:

1. Previously received TAK-788.

2. Received small-molecule anticancer therapy (including cytotoxic chemotherapy, and investigational agents, = 14 days prior to first dose of TAK-788 (except for reversible EGFR TKIs [that is, erlotinib or gefitinib], which are allowed in the dose escalation and expansion cohorts up to 7 days prior to the first dose of TAK-788).

3. Received antineoplastic monoclonal antibodies including immunotherapy within 28 days of the first dose of TAK-788.

4. Have been diagnosed with another primary malignancy other than NSCLC except for adequately treated non-melanoma skin cancer or cervical cancer in situ; definitively treated non-metastatic prostate cancer; or participants with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy.

Note: This exclusion criteria does not apply to Expansion Cohort 7.

5. Received radiotherapy <=14 days prior to the first dose of TAK-788 or has not recovered from radiotherapy-related toxicities. Palliative radiation administered outside the chest and brain, stereotactic radiosurgery (SRS), and stereotactic body radiotherapy are allowed up to 7 days prior to the first dose

6. Received a moderate or strong CYP4503A inhibitor or moderate or strong CYP3A inducer within 10 days prior to first dose of TAK-788.

7. Have undergone major surgery within 28 days prior to first dose of TAK-788. Minor surgical procedures, such as catheter placement or minimally invasive biopsy, are allowed.

8. Part 1 (dose escalation) and Expansion Cohorts 1 to 3 of Part 2 (expansion phase) only:

Have symptomatic CNS metastases at screening or asymptomatic disease requiring corticosteroids to control symptoms within 7 days prior to the first dose of TAK-788.

Part 3 (extension cohort) and Expansion Cohorts 4 to 7 of Part 2 (expansion phase) only:

Have known active brain metastases (have either previously untreated intracranial CNS metastases or previously treated intracranial CNS metastases with radiologically documented new or progressing CNS lesions). Brain metastases are allowed if they have been treated with surgery and/or radiation and have been stable without requiring corticosteroids to control symptoms within 7 days before the first dose of TAK-788, and have no evidence of new or enlarging brain metastases.

9. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging) or leptomeningeal disease (symptomatic or asymptomatic).

10. Have significant, uncontrolled, or active cardiovascular disease.

11. Have a known history of uncontrolled hypertension. Participants with hypertension should be under treatment on study entry to control blood pressure.

12. Have prolonged QTcF interval, or being treated with medications known to be associated with the development of torsades de pointes.

13. Have an ongoing or active infection, including but not limited to, the requirement for intravenous (IV) antibiotics, or a known history of human immunodeficiency virus, hepatitis B virus (HBV), or hepatitis C virus (HCV). Testing is not required in the absence of history.

14. Currently have or have a history of interstitial lung disease, radiation pneumonitis that required steroid treatment, or drug-related pneumonitis.

15. Female participants who are lactating and breastfeeding or have a positive urine or serum pregnancy test during the screening period.

Note: Female participants who are lactating will be eligible if they discontinue breastfeeding.

16. Have gastrointestinal illness or disorder that could affect oral absorption of TAK-788.

17. Have any condition or illness that, in the opinion of the investigator, might compromise participant safety or interfere with the evaluation of the safety of the drug.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung

Intervention

Drug:
• TAK-788
TAK-788 capsules.

Locations

Country	Name	City	State
China	Beijing Chest Hospital	Beijing	Beijing
China	Peking University Cancer Hospital/Beijing Cancer Hospital	Beijing	Beijing
China	The First Affiliated Hospital, Zhejiang University	Hangzhou	Zhejiang
China	Shanghai Pulmonary Hospital	Shanghai	Shanghai
China	Hubei Cancer Hospital	Wuhan	Hubei
Germany	HELIOS Klinikum Emil von Behring	Berlin
Germany	Thoraxklinik Heidelberg	Heidelberg	Baden-wuerttemberg
Italy	Istituto Di Ricovero E Cura A Carattere Scientifico - Istituto Europeo Di Oncologia	Milano
Italy	Azienda Ospedaliero Universitaria di Parma	Parma
Japan	National Cancer Center Hospital East	Kashiwa	Chiba
Japan	Kurume University Hospital	Kurume-shi	Fukuoka
Japan	Kindai University Hospital	Osaka-sayama	Osaka
Japan	Sendai Kousei Hospital	Sendai	Miyagi
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggi-do
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital	Seoul
Puerto Rico	In Situ Global Clinical Trials Network	Manati
Spain	Complejo Hospitalario Universitario A Coruna	A Coruna	LA Coruna
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Taiwan	National Taiwan University Hospital - YunLin Branch	Douliu	Yunlin
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Cheng Kung University Hospital	Tainan	Tainan CITY
Taiwan	National Taiwan University Hospital	Taipei
United Kingdom	The Royal Marsden NHS Foundation Trust	London	England
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Winship Cancer Institute	Atlanta	Georgia
United States	University of Colorado Cancer Center	Aurora	Colorado
United States	Brookwood Medical Center	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Carolinas Healthcare System	Charlotte	North Carolina
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	The University of Chicago Medicine	Chicago	Illinois
United States	City of Hope Comprehensive Cancer Center - Duarte	Duarte	California
United States	Virginia Cancer Specialists - Fairfax Office	Fairfax	Virginia
United States	Compassionate Cancer Care - Fountain Valley	Fountain Valley	California
United States	Banner MD Anderson Cancer Center	Gilbert	Arizona
United States	Lumi Research	Houston	Texas
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Investigative Clinical Research - Indiana	Indianapolis	Indiana
United States	Thompson Oncology Group - Knoxville - Downtown	Knoxville	Tennessee
United States	University of California San Diego Moores Cancer Center	La Jolla	California
United States	Pacific Shores Medical Group-Long Beach Elm	Long Beach	California
United States	Cancer and Blood Specialty Clinic	Los Alamitos	California
United States	Atlantic Health - Morristown Medical Center	Morristown	New Jersey
United States	SCRI - Tennessee Oncology - Nashville - Centennial	Nashville	Tennessee
United States	University of Virginia Cancer Center	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Hightower Clinical	Oklahoma City	Oklahoma
United States	University of California Irvine Health Chao Family Comprehensive Cancer Center	Orange	California
United States	AdventHealth Orlando	Orlando	Florida
United States	Stanford Cancer Center - Palo Alto	Palo Alto	California
United States	Oregon Health and Science University	Portland	Oregon
United States	Siteman Cancer Center - Washington University Medical Campus	Saint Louis	Missouri
United States	SLO Oncology and Hematology Health Center	San Luis Obispo	California
United States	Swedish Cancer Institute	Seattle	Washington
United States	The Oncology Institute of Hope and Innovation - West Tucson	Tucson	Arizona
United States	The Oncology Institute of Hope and Innovation	Whittier	California

Sponsors (1)

Lead Sponsor	Collaborator
Takeda

Countries where clinical trial is conducted

United States,  China,  Germany,  Italy,  Japan,  Korea, Republic of,  Puerto Rico,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1, Dose Escalation Component: Recommended Phase 2 Dose (RP2D) of Orally Administered TAK-788		Cycle 1 (Cycle length is equal to [=] 28 days)
Primary	Part 2, Expansion Cohorts 1, 2, 4, 5 and 7: Confirmed Objective Response Rate (ORR) Assessed by the Investigator		Up to 36 months after first dose
Primary	Part 2, Expansion Cohort 3: Intracranial ORR (iORR) Assessed by Independent Review Committee (IRC)		Up to 36 months after first dose
Primary	Part 2, Expansion Cohort 6: Confirmed ORR Assessed by IRC		Up to 36 months after first dose
Primary	Part 3, Extension Cohort: Confirmed ORR Assessed by IRC		Up to 36 months after first dose
Secondary	Part 1, Dose Escalation Component: Dose Limiting Toxicities (DLTs) of TAK-788		Cycle 1 (Cycle length=28 days)
Secondary	Part 1, Dose Escalation Component: Maximum Tolerated Dose (MTD) of TAK-788		Cycle 1 (Cycle length=28 days)
Secondary	Parts 1 and 2, Dose Escalation and Expansion Cohorts: Cmax; Maximum Observed Concentration of TAK-788 and its Metabolites		Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days for Parts 1 and 2)
Secondary	Parts 1 and 2, Dose Escalation and Expansion Cohorts: Tmax; Time of First Occurrence of Maximum Plasma Concentration (Cmax) of TAK-788 and its Metabolites		Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days for Parts 1 and 2)
Secondary	Parts 1 and 2, Dose Escalation and Expansion Cohorts: AUC 24; Area Under the Concentration-time Curve from Time Zero to 24 hours for TAK-788 and its Metabolites		Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days for Parts 1 and 2)
Secondary	Parts 1 and 2, Dose Escalation and Expansion Cohorts: AUCt: Area Under the Concentration-time Curve from Time Zero to Time t for TAK-788 and its Metabolites		Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days for Parts 1 and 2)
Secondary	Parts 1 and 2, Dose Escalation and Expansion Cohorts: RAC (Cmax): Accumulation Ratio Based on Cmax of TAK-788 and its Metabolites		Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days for Parts 1 and 2)
Secondary	Parts 1 and 2, Dose Escalation and Expansion Cohorts: RAC (AUC): Accumulation Ratio Based on AUC of TAK-788 and its Metabolites		Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days for Parts 1 and 2)
Secondary	Part 2, Expansion Cohorts 1, 2, 3, 4, 5, and 7: Confirmed ORR as Assessed by IRC		Up to 36 months after first dose
Secondary	Part 2, Expansion Cohorts: Best Overall Response as Assessed by the Investigator and IRC		Up to 36 months after first dose
Secondary	Part 2, Expansion Cohorts: Best Target Lesion Response as Assessed by the Investigator and IRC		Up to 36 months after first dose
Secondary	Parts 2 and 3, Expansion and Extension Cohorts: Duration of Response as Assessed by the Investigator and IRC		Up to 36 months after first dose
Secondary	Parts 2 and 3, Expansion and Extension Cohorts: Disease Control Rate (DCR) as Assessed by the Investigator and IRC		Up to 36 months after first dose
Secondary	Part 2 and 3, Expansion and Extension Cohorts: Time to Response as Assessed by the Investigator and IRC		Up to 36 months after first dose
Secondary	Parts 2 and 3, Expansion and Extension Cohorts: Progression Free Survival (PFS) as Assessed by the Investigator and IRC		Up to 36 months after first dose
Secondary	Parts 2 and 3, Expansion and Extension Cohorts: Overall Survival (OS)		Up to 36 months after first dose
Secondary	Part 2, Expansion Cohort 3: Duration of Intracranial Response (iDOR)		up to 36 months after first dose
Secondary	Part 2, Expansion Cohort 3: Intracranial PFS (iPFS)		up to 36 months after first dose
Secondary	Part 2, Expansion Cohorts 6: Confirmed ORR as Assessed by the Investigator		Up to 36 months after first dose
Secondary	Part 3, Extension Cohort: Confirmed ORR as Assessed by the Investigator		Up to 36 months after first dose
Secondary	Part 3, Number of Participants With Patient-reported Symptoms (Lung Cancer), Functioning, and Health-related Quality of Life (HRQoL) Based on European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30)		Up to 30 days after last dose of drug (approximately up to 37 months)
Secondary	Part 3, Extension Cohort: Number of Participants With Patient-reported Symptoms (Lung Cancer), Functioning, and health-related Global Quality of Life (HRQoL) Based on Quality of Life Questionnaire Lung Cancer Module-13 (QLQ-LC13)		Up to 30 days after last dose of drug (approximately up to 37 months)

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