Clinical Trial Details
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NCT01449461 : A Phase 1/2 Study of the Oral ALK/EGFR Inhibitor AP26113
PhasePhase 1/Phase 2
AgesMin: 18 Years Max: N/A
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

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

- 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

- 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

- 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

- 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.
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