Patient case: 45-year-old female with Melanoma. Genetic variant: BRAF (V600E), CDKN2A Deletion. Other conditions: None.

Clinical trial: A Trial of AP32788 in Non-Small Cell Lung Cancer

Summary: The purpose of this phase 1/2 study is to evaluate the safety, pharmacokinetics, and anti-tumor activity of oral AP32788 in patients with non-small cell lung cancer (NSCLC). The trial will be conducted in two parts: a dose escalation phase, followed by an expansion phase. The goal of the dose escalation phase is to determine the safety profile of orally administered AP32788, including the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), recommended phased 2 dose (RP2D) and pharmacokinetic profile. Once the RP2D is established, the expansion phase will assess the preliminary anti-tumor activity of AP32788 in 4 histologically and molecularly defined NSCLC cohorts. Approximately 105 patients will be enrolled.

Detailed description: This phase 1/2 study will evaluate the safety, pharmacokinetics, and anti-tumor activity of oral EGFR/HER2 Inhibitor AP32788 in patients with non-small cell lung cancer (NSCLC). The trial will be conducted in two parts: a dose escalation phase, followed by an expansion phase.
  The objectives of the dose escalation phase are to determine the safety profile of orally administered AP32788, including the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), recommended phase 2 dose (RP2D) and pharmacokinetic profile.
  The primary goal of the expansion component of the trial is to evaluate the anti-tumor activity of AP32788 in four histologically and molecularly defined cohorts at the RP2D (determined based on dose escalation phase of the trial).
  The four expansion cohorts will be:
  1. NSCLC patients with EGFR exon 20 activating insertions and no active, measurable central nervous system (CNS) metastases;
  2. NSCLC patients with HER2 exon 20 activating insertions or point mutations and no active, measurable CNS metastases;
  3. NSCLC patients with EGFR exon 20 activating insertions or HER2 exon 20 activating insertions or point mutations and active, measurable CNS metastases; and
  4. NSCLC patients with other targets against which AP32788 is active (examples include EGFR exon 19 deletions or exon 21 substitutions [with or without T790M mutations] and other uncommon EGFR activating mutations), with or without active, measurable CNS metastases.

Eligibility: General Inclusion Criteria (all dose escalation and expansion cohorts):
  1. Have histologically or cytologically confirmed locally advanced (and not a candidate for definitive therapy) or metastatic NSCLC (Stage IIIB or IV).
  2. Must have sufficient tumor tissue available for analysis (see Study Reference Manual for specific requirements). For patients in the expansion cohorts, tumor tissue obtained after progression on the most recent prior therapy is preferred.
  3. Must have measurable disease by RECIST v1.1
  4. Male or female patients ≥18 years old.
  5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
  6. Minimum life expectancy of 3 months or more.
  7. Adequate renal and hepatic function as defined by the following criteria:
  1. Total serum bilirubin ≤2 × upper limit of normal (ULN);
  2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN (or ≤5 × ULN if liver function abnormalities are due to underlying malignancy);
  3. Estimated creatinine clearance ≥ 60 mL/min (calculated by using the Cockcroft-Gault equation); and
  4. Serum albumin ≥2 g/dL.
  8. Adequate bone marrow function as defined by the following criteria:
  e. Absolute neutrophil count (ANC) ≥1.5 × 109/L; f. Platelet count ≥75 × 109/L; and g. Hemoglobin ≥9.0 g/dL.
  9. Normal QT interval on screening electrocardiogram (ECG), defined as QT interval corrected (Fridericia) (QTcF) of ≤450 ms in males or ≤470 ms in females.
  10. All toxicities from prior therapy have resolved to ≤ grade 1 according to the NCI CTCAE v4.0, or have resolved to baseline, at the time of first dose of AP32788.
  11. For females of childbearing potential, a negative pregnancy test must be documented prior to enrollment.
  12. Female patients who are of childbearing potential and fertile male patients must agree to use a highly effective form of contraception with their sexual partners throughout study participation.
  13. Signed and dated informed consent indicating that the patient has been informed of all pertinent aspects of the study.
  14. Willingness and ability to comply with scheduled visits and study procedures.
  Dose Escalation Cohort Specific Inclusion Criteria:
  1. Refractory to standard available therapies.
  Expansion Cohort 1 Specific Inclusion Criteria:
  1. Have a documented EGFR in-frame exon 20 insertion by a local test, including A763_Y764insFQEA, V769_D770insASV, D770_N771insNPG, D770_N771insSVD, H773_V774insNPH, or any other in-frame exon 20 insertion mutation.
  2. Previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease.
  3. Have not received a tyrosine kinase inhibitor (TKI) with activity against the specific documented EGFR exon 20 insertion.
  4. Not eligible for Expansion Cohort 3.
  Expansion Cohort 2 Specific Inclusion Criteria:
  1. Have one of the following documented by a local test:
  1. A HER2 exon 20 insertion including A775_G776insYVMA, G776_V777insVC, or P780_Y781insGSP, or any other in-frame exon 20 insertion mutation.
  2. An activating point mutation in HER2 including, but not limited to, L755S, G776V, and V777L.
  2. Previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease.
  3. Have not received a TKI with pan-HER activity (eg, afatinib, neratinib, or dacomitinib).
  4. Not eligible for Expansion Cohort 3.
  Expansion Cohort 3 Specific Inclusion Criteria:
  1. Have one of the following documented by a local test:
  1. An EGFR exon 20 insertion: A763_Y764insFQEA, V769_D770insASV, D770_N771insNPG, D770_N771insSVD, H773_V774insNPH, or any other in-frame exon 20 insertion mutation.
  2. A HER2 exon 20 insertion: A775_G776insYVMA, G776_V777insVC, P780_Y781insGSP, or any other in-frame exon 20 insertion mutation.
  3. An activating point mutation in HER2 including, but not limited to, L755S, G776V, and V777L.
  2. Previously treated with one or more regimen of systemic therapy for locally advanced or metastatic disease.
  3. For patients with an EGFR exon 20 insertion: have not received a TKI with activity against the specific documented EGFR exon 20 insertion.
  4. For patients with a HER2 exon 20 insertion or HER2 activating point mutation: have not received a TKI with pan-HER activity (eg, afatinib, neratinib, or dacomitinib).
  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 (ie, measurable) intracranial CNS lesion (≥10 mm in longest diameter by contrast enhanced magnetic resonance imaging [MRI]). Lesions previously treated by stereotactic radiosurgery (SRS) or surgical resection should not be included as a target lesion. Lesions previously treated with whole brain radiation therapy (WBRT) may be included as a target lesion if (1) the last administration of WBRT was >3 months prior to the first dose of AP32788 and (2) unequivocal radiological progression of the lesion has been observed.
  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. Previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease.
  3. For patients with a documented EGFR exon 19 deletion or exon 21 L858R substitution: resistant to at least one prior EGFR inhibitor (eg, erlotinib, gefitinib, or afatinib).
  4. For patients with a documented EGFR T790M mutation: have not received a TKI with activity against the EGFR T790M mutation.
  5. For patients with an uncommon activating mutation in EGFR: have not received a TKI with activity against the specific documented uncommon activating mutation.
  6. Have or do not have active (untreated or progressing) CNS metastases.
  Exclusion Criteria:
  1. Received systemic anticancer therapy (including cytotoxic chemotherapy, investigational agent, antineoplastic monoclonal antibodies, or immunotherapy) ≤14 days prior to first dose of AP32788 (except for reversible EGFR TKIs [ie, erlotinib or gefitinib], which are allowed up to 7 days prior to the first dose of AP32788).
  2. Have been diagnosed with another primary malignancy other than NSCLC except for adequately treated non-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.
  3. Received radiotherapy ≤14 days prior to the first dose of AP32788 of study drug.
  4. Received a potent CYP3A inhibitor within 7 days or potent CYP3A inducer within 5 weeks prior to first dose of AP32788.
  5. Have undergone major surgery within 28 days prior to first dose of AP32788. Minor surgical procedures, such as catheter placement or minimally invasive biopsy, are allowed.
  6. Have brain metastases that are neurologically unstable or require an increasing dose of corticosteroids. Patients must be on a stable or decreasing dose of corticosteroids for 7 days prior to first dose of AP32788.
  7. Have symptomatic leptomeningeal carcinomatosis or spinal cord compression. Patients with asymptomatic leptomeningeal disease and no evidence of spinal cord compression are allowed.
  8. Have significant, uncontrolled, or active cardiovascular disease, including, but not restricted to:
  1. Myocardial infarction (MI) within 6 months prior to the first dose of study drug;
  2. Unstable angina within 6 months prior to first dose;
  3. Congestive heart failure (CHF) within 6 months prior to first dose;
  4. History of clinically significant (as determined by the treating physician) atrial arrhythmia;
  5. Any history of ventricular arrhythmia; or
  6. Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose.
  9. Have a known history of uncontrolled hypertension. Patients with hypertension should be under treatment on study entry to control blood pressure.
  10. Have prolonged QTcF interval, or being treated with medications known to be associated with the development of Torsades de Pointes.
  11. 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 (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Testing is not required in the absence of history.
  12. Currently have or have a history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis that required steroid treatment.
  13. Are pregnant or breastfeeding.
  14. Have gastrointestinal illness or disorder that could affect oral absorption of AP32788 (such as short gut syndrome, Crohn's disease, ulcerative colitis, or CTCAE grade 2 or greater diarrhea of any etiology at baseline).
  15. 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.

Relevance to patient case: not relevant