A Study of Mobocertinib in Japanese Adults With Non-Small Cell Lung Cancer

A Phase 1/2 Study of the Oral EGFR/HER2 Inhibitor TAK-788 in Japanese Non-Small Cell Lung Cancer Patients

This study is in 2 parts. Different participants will take part in the 1st and 2nd parts of the study.

The main aim of the 1st part of the study is to check how much Mobocertinib adults with non-small cell lung cancer (NSCLC) can receive without getting side effects from it.

The main aim of the 2nd part of the study is to learn if the condition of adults with non-small cell lung cancer improves after treatment with Mobocertinib. Another aim is to continue checking for side effects from Mobocertinib.

In the 1st part of the study, at the first visit, the study doctor will check who can take part. For those that can take part, participants will take a capsule of Mobocertinib once a day for 28 days. This will count as 1 cycle. Different small groups of participants will receive lower to higher doses of Mobocertinib. The study doctors will check for side effects after each dose of TAK 788. In this way, researchers can work out the best dose of Mobocertinib to give participants in the 2nd part of the study.

Participants will visit the clinic 30 days after their treatment has finished for a final check-up.

In the 2nd part of the study, at the first visit, the study doctor will check who can take part. Participants will receive the best dose of Mobocertinib worked out from the 1st part of the study. Participants will receive Mobocertinib in the same way as those from the 1st part of the study. The study doctors will learn if the condition of these participants improves after treatment with Mobocertinib. The study doctors will also check for side effects from Mobocertinib.

After treatment has finished, participants will visit the clinic every 12 weeks until the end of the study.

In both parts of the study, participants can receive Mobocertinib for up to just over 1 year, or longer if their condition stays improved.

The drug being tested in this study is called Mobocertinib. Mobocertinib is being tested to treat Japanese participants with NSCLC. This study has two parts (Phase 1 part and Phase 2 part), Phase 1 part of this study will look at the safety, efficacy, tolerability and PK of Mobocertinib orally administered once daily, and will determine a RP2D. Phase 2 study will look at the efficacy and safety of Mobocertinib in treatment naive Japanese NSCLC patients with epidermal growth factor receptor (EGFR) exon 20 insertion mutation. All participants will be assigned to Phase 1 part or Phase 2 part and will be asked to take Mobocertinib capsule as following dosage and regimen;

Phase 1 part; Mobocertinib, 40 mg as starting dose, once daily, and escalating up to 160 mg until a Maximum Tolerated Dose (MTD). An expansion phase may be followed at any dose to further confirm safety observations following identification of MTD/RP2D.

Phase 2 part; Mobocertinib, 160 mg, once daily

The study will enroll approximately 58-63 participants (Phase 1 part; 28-33 and Phase 2 part; 30).

This multi-center trial will be conducted in Japan. The overall time to participate in this study of Phase 1 part is approximately 3 years and Phase 2 part is approximately 4 years. Participants will make multiple visits to the clinic in the treatment period, and the post-treatment period including follow-up assessments after the last dose of the study drug.

Inclusion Criteria:

General Inclusion Criteria (Both in Phase 1 and Phase 2 Part);

1. Male or female patients ≥20 years old.

2. Must have measurable disease by RECIST v1.1. Previously irradiated lesions may not be used for target lesions, unless there is unambiguous radiological progression after radiotherapy.

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

4. Minimum life expectancy of 3 months or more.

5. Adequate renal and hepatic function as defined by the following criteria:

   •Total serum bilirubin ≤1.5 × upper limit of normal (ULN) (≤3.0 × ULN for patients with Gilbert syndrome or if liver function abnormalities are due to underlying malignancy);

   •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN (or ≤5 × ULN if liver function abnormalities are due to underlying malignancy);

   •Estimated creatinine clearance ≥30 mL/min (calculated by using the Cockcroft-Gault equation);

   •Serum albumin ≥2 g/dL; and

   •Serum lipase ≤1.5 × ULN; and

   •Serum amylase ≤1.5 × ULN unless the increased serum amylase is due to salivary isoenzymes.

6. Adequate bone marrow function as defined by the following criteria:

   • Absolute neutrophil count ≥1.5 × 109/L;
   • Platelet count ≥75 × 109/L in Phase 1 Part and ≥100 × 109/L in Phase 2 Part; and
   • Hemoglobin ≥9.0 g/dL.

7. Normal QT interval on screening ECG, defined as QTcF of ≤450 ms in males or ≤470 ms in females.

8. Female patients who:

   • Are postmenopausal (natural amenorrhea and not due to other medical reasons) for at least 1 year before the screening visit, OR
   • Are surgically sterile, OR
   • If they are of childbearing potential, agree to practice 1 highly effective non-hormonal method of contraception and 1 additional effective (barrier) method (see Section 8.7.1) at the same time, from the time of signing the informed consent form (ICF) through 30 days after the last dose of study drug, OR
   • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject.

Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.

Male patients, even if surgically sterilized (ie, status postvasectomy), who:

• Agree to practice effective barrier contraception during the entire study treatment period and through 30 days after the last dose of study drug, OR
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject.

Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.

9.Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

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

• Phase-Specific Inclusion Criteria (Phase 1 part);

  1.Have histologically or cytologically confirmed locally advanced (and not a candidate for definitive therapy) (Stage IIIB) or metastatic NSCLC (Stage IV).

  2.Refractory to standard available therapies. 3.All toxicities from prior therapy have resolved to ≤ grade 1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0), or have resolved to baseline, at the time of first dose of Mobocertinib. Note: treatment-related grade >1 alopecia or treatment-related grade 2 peripheral neuropathy are allowed if deemed irreversible.

• Phase-Specific Inclusion Criteria (Phase 2 part);

  1. Histologically or cytologically confirmed locally advanced not suitable for definitive therapy, recurrent, or metastatic (Stage IV) NSCLC.

  2. Not received prior systemic treatment for locally advanced or metastatic disease (with the exception below): Neoadjuvant or adjuvant chemotherapy/immunotherapy for Stage I to III or combined modality chemotherapy/radiation for locally advanced disease is allowed if completed >6 months before the development of metastatic disease.

  3. A documented EGFR in-frame exon 20 insertion (including A763_Y764insFQEA, V769_D770insASV, D770_N771insNPG, D770_N771insSVD, H773_V774insNPH, or any other in-frame exon 20 insertion mutation) by a local test that has been analytically validated per local authority guidelines. The EGFR exon 20 insertion mutation can be either alone or in combination with other EGFR or HER2 mutations except EGFR common mutations (exon 19 del or L858R).

  4. Adequate tumor tissue available, either from primary or metastatic sites, for central laboratory confirmation of EGFR in-frame exon 20 insertion mutation. Note: confirmation of central test positivity is not required before the first dose of Mobocertinib.

     Exclusion Criteria:

     General Exclusion Criteria (Both in Phase 1 and Phase 2 Part);

  1. 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 patients with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy.
  2. Have undergone major surgery within 28 days prior to first dose of Mobocertinib. Minor surgical procedures, such as catheter placement or minimally invasive biopsy, are allowed.
  3. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging) or leptomeningeal disease (symptomatic or asymptomatic).
  4. Have significant, uncontrolled, or active cardiovascular disease, including, but not restricted to:

• Myocardial infarction within 6 months prior to the first dose of study drug;

• Unstable angina within 6 months prior to first dose;

• Congestive heart failure within 6 months prior to first dose;

• History of clinically significant (as determined by the treating physician) atrial arrhythmia;

• Any history of ventricular arrhythmia; or

• Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose.

  5.Have uncontrolled hypertension. Patients with hypertension should be under treatment on study entry to control blood pressure.

  6.Currently being treated with medications known to be associated with the development of Torsades de Pointes.

  7.Have an ongoing or active infection, including, but not limited to, the requirement for intravenous antibiotics. Have a known history of HIV infection. Testing of HIV is not required in the absence of history.Hepatitis B surface antigen (HBsAg) positive patients are allowed to enroll if hepatitis B virus (HBV)-DNA is below 1000 copies/mL in the plasma.Patients who have positive hepatitis C virus (HCV) antibody can be enrolled but must have HCV-RNA undetectable in the plasma.

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

  9.Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the screening period.

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

  10.Have gastrointestinal illness or disorder that could affect oral absorption of Mobocertinib.

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

• Phase-Specific Exclusion Criteria (Phase 1 part);

  1. Previously received Mobocertinib.

  2. Received small-molecule anticancer therapy (including cytotoxic chemotherapy and investigational agents) within 14 days prior to the first dose of Mobocertinib (except for reversible EGFR TKIs [ie, erlotinib or gefitinib] up to 7 days prior to the first dose of Mobocertinib).

  3. Received antineoplastic monoclonal antibodies including immunotherapy within 28 days prior to the first dose of Mobocertinib.

  4. Received radiotherapy within 14 days prior to the first dose of Mobocertinib, Stereotactic radiosurgery (SRS) and stereotactic body radiosurgery are allowed up to 7 days prior to the first dose.

  5. Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening or asymptomatic disease requiring corticosteroids to control symptoms within 7 days prior to the first dose of Mobocertinib.

     Note: If a patient has worsening neurological symptoms or signs due to CNS metastases, the patient needs to complete local therapy and be neurologically stable (with no requirement for corticosteroids or use of anticonvulsants) for 7 days prior to the first dose of Mobocertinib. Patients with no prior history of signs or symptoms of CNS metastases but who receive prophylactic steroids or anticonvulsants are allowed.

  6. Received a strong cytochrome P450 (CYP)3A inhibitor or strong CYP3A inducer within 2 weeks prior to first dose of Mobocertinib.

• Phase-Specific Exclusion Criteria (Phase 2 part);

  1. Received radiotherapy within 14 days before the first dose of Mobocertinib or has not recovered from radiotherapy-related toxicities. Stereotactic radiosurgery, stereotactic body radiotherapy, or palliative radiation outside the chest and brain is allowed up to 7 days before the first dose of Mobocertinib.
  2. 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 Mobocertinib, and have no evidence of new or enlarging brain metastases.
  3. Received a moderate or strong CYP3A inhibitor or moderate or strong CYP3A inducer within 10 days prior to first dose of Mobocertinib.
  4. Have cardiac ejection fraction <50% by echocardiogram or multigated acquisition (MUGA) scan at screening.