Patient case: 71-year-old female with lung cancer; genetic feature: ROS1

Clinical trial: A Phase 1/2 Study of the Oral ALK/EGFR Inhibitor AP26113

Summary: The purpose of this study is 2-fold: initially, in the dose escalation phase, the goal is to determine the safety profile of orally administered AP26113, including: the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), recommended phase 2 dose (RP2D), and pharmacokinetic (PK) profile. Then, once the RP2D is established, an expansion phase will assess the preliminary anti-tumor activity of AP26113, both in non-small cell lung cancer (NSCLC) with ALK gene rearrangement (including patients with active brain metastases)or mutated EGFR, and in other cancers with abnormal targets against which AP26113 is active. Approximately 135 to 175 patients will be enrolled.

Detailed description: This is the first assessment of AP26113 in patients. The trial will be conducted in 2 parts: an initial dose escalation phase in 30 to 70 patients with advanced malignancies (all histologies other than leukemia), resistant to available therapies or for whom no standard or available curative treatments exist, followed by an expansion phase in 5 histologically and molecularly defined cohorts of patients (approximately 20-25 patients per cohort, approximately 105 patients altogether). The objectives of the dose escalation phase are to determine the safety, tolerability, pharmacokinetic profile, and recommended phase 2 dose (RP2D) of orally administered AP26113. The objectives of the expansion phase are to describe the preliminary anti-tumor activity (overall response rate) of AP26113 in patients with non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) gene rearrangement or mutated epidermal growth factor receptor (EGFR), and in patients with any cancers with abnormalities in ALK or other targets against which AP26113 is active, and to continue to assess safety and tolerability.

Eligibility: Patients must meet all the criteria for the cohort for which their entry is proposed.
  PART 1: Dose Escalation Phase:
  1. Histologically confirmed advanced malignancies. All histologies except leukemia;
  2. Refractory to available therapies or for whom no standard or available curative treatments exist;
  3. Tumor tissue available for analysis;
  PART 2: Expansion cohorts (5 additional cohorts):
  1. Expansion cohort 1: Non-small cell lung cancer (NSCLC) patients whose tumors exhibit anaplastic lymphoma kinase (ALK) rearrangements and who have not been treated with previous ALK inhibitors.
  -  Histologically or cytologically confirmed NSCLC;
  -  Tumor tissue available for analysis (see General Eligibility Criterion 1;
  -  History of ALK rearrangement by fluorescence in situ hybridization (FISH);
  -  No prior ALK inhibitor therapy;
  2. Expansion cohort 2: NSCLC patients whose tumors exhibit ALK rearrangements and who are resistant to crizotinib:
  -  Histologically or cytologically confirmed NSCLC;
  -  Tumor tissue available for analysis (see General Eligibility Criterion 1);
  -  History of ALK rearrangement by FISH;
  -  Resistant to crizotinib (and have not received any other prior ALK inhibitor therapy);
  3. Expansion cohort 3: NSCLC patients whose tumors exhibit an epidermal growth factor receptor EGFR-T790M mutation and who are resistant to 1 prior EGFR TKI:
  -  Histologically or cytologically confirmed NSCLC
  -  Previous treatment with only 1 EGFR TKI for which the last administration was within 30 days of the initiation of AP26113;
  -  Documented evidence of an EGFR-T790M mutation following disease progression on the most recent EGFR TKI therapy;
  -  No intervening systemic therapy between cessation of the EGFR TKI and initiating AP26113;
  -  Tumor tissue available for analysis (see General Eligibility Criterion 1).
  4. Expansion cohort 4: Patients with any cancers with abnormalities in ALK or other AP26113 targets. Examples include, but are not limited to, anaplastic large cell lymphoma (ALCL), diffuse large-cell lymphoma (DLCL), inflammatory myofibroblastic tumors (IMT), and other cancers with ALK abnormalities, or tumors with ROS1 fusions:
  -  Histologically confirmed lymphomas and other cancers, with the exception of leukemias;
  -  Tumor tissue available for analysis (see General Eligibility Criterion 1).
  5. Expansion Cohort 5: NSCLC patients whose tumors exhibit ALK rearrangements and who have active, measurable brain metastases:
  -  Histologically or cytologically confirmed NSCLC:
  -  Tumor tissue available for analysis (see General Eligibility Criterion 1);
  -  History of ALK rearrangement by FISH;
  -  Either crizotinib naive or resistant;
  -  Have at least one measurable brain lesion (≥ 10 mm by contrast enhanced, T1 weighted magnetic resonance imaging [cMRI]). Previously treated brain lesions by stereotactic radiosurgery (SRS) or surgical resection should not be included as a target or non-target lesion;
  -  Previously untreated brain metastases with radiologically documented new or progressing brain lesions. Unequivocal progression of previously treated lesions (non-SRS and non-surgically treated lesions) at least 3 months after the last treatment;
  -  Neurologically stable. Patients must be on a stable or deceasing dose of corticosteroids and/or have no requirement for anticonvulsants for 5 days prior to the baseline MRI and for 5 days prior to initiating AP26113.
  General Eligibility Criteria:
  All patients (irrespective of whether they are enrolled in PART 1 or PART 2) must meet all the following eligibility criteria for study entry.
  -  All patients must have tumor tissue available for analysis. If sufficient tissue is not available, patients must undergo a biopsy to obtain adequate samples. For patients in expansion cohorts 2, 3 and 5, for whom failure of prior therapy is specified (crizotinib for cohorts 2 and 5, one EGFR-TKI for cohort 3),tumor tissue must be available following failure of the prior therapy.
  -  Must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST).
  -  Male or female patients ≥ 18 years old.
  -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  -  Minimum life expectancy of 3 months or more.
  -  Adequate renal and hepatic function.
  -  Adequate bone marrow function.
  -  Normal QT interval on screening electrocardiogram (ECG) evaluation.
  -  For females of childbearing potential, a negative pregnancy test must be documented prior to enrollment.
  -  Female patients who are of childbearing potential and fertile male patients must agree to use an effective form of contraception with their sexual partners throughout study participation.
  -  Signed and dated informed consent indicating that the patient has been informed of all pertinent aspects of the study.
  -  Willingness and ability to comply with scheduled visits and study procedures.
  Main Exclusion Criteria:
  -  Received an investigational agent ≤ 14 days prior to initiating AP26113.
  -  Received systemic anticancer therapy (including monoclonal antibodies and irreversible TKIs such as afatinib or dacomitinib) or radiation therapy ≤ 14 days prior to initiating AP26113.
  -  Except for a reversable TKI (ie, erlotinib or gefitinib) or crizotinib, which are allowed up to 72 hours prior to initiating AP26113, provided that the patient is free of treatment-related toxicity that might confound the safety evaluation of AP26113.
  -  Received any prior agents targeted against ALK, with the exception of crizotinib, or received more than 1 prior EGFR TKI.
  -  Re-challenge with the same TKI is allowed.
  -  Major surgery within 28 days prior to initiating AP26113.
  -  Brain metastases that are neurologically unstable or require anticonvulsants or an increasing dose of corticosteroids.
  -  Patients with previously treated brain metastases without evidence of disease or recurrence are allowed for cohorts 1-4.
  -  Patients with evaluable but non-measurable, active brain lesions who otherwise meet the criteria for cohort 5 for CNS disease can be enrolled in other cohorts.
  -  Significant uncontrolled or active cardiovascular disease.
  -  Uncontrolled hypertension (diastolic blood pressure [BP] > 100 mm Hg; systolic > 150 mm Hg).
  -  Prolonged QT interval, or being treated with medications known to cause Torsades de Pointes.
  -  History or presence of pulmonary interstitial disease or drug-related pneumonitis.
  -  Ongoing or active infection. The requirement for intravenous (IV) antibiotics is considered active infection.
  -  Known history of human immunodeficiency virus (HIV). Testing is not required in the absence of history.
  -  Pregnant or breastfeeding.
  -  Malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of AP26113.
  -  Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the safety of the drug.
  -  Leptomeningeal carcinomatosis and spinal cord compression. In the case of suspected meningeal involvement, a negative lumbar puncture prior to study entry is required.

Relevance to patient case: not relevant