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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Ariad Pharmaceuticals
Sponsor:
Information provided by (Responsible Party):
Ariad Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01449461
First received: September 30, 2011
Last updated: April 11, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Advanced Malignancies
Carcinoma, Non-Small-Cell Lung
Anaplastic Large Cell Lymphoma
Diffuse Large Cell Lymphoma
Inflammatory Myofibroblastic Tumors
Drug: AP26113
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of the Oral ALK/EGFR Inhibitor AP26113

Resource links provided by NLM:


Further study details as provided by Ariad Pharmaceuticals:

Primary Outcome Measures:
  • Recommended Phase 2 Dose (RP2D) [ Time Frame: Day 1 to 28 (Cycle 1) ] [ Designated as safety issue: Yes ]
  • Overall response rate [ Time Frame: Up to 24 months after first dose ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Maximum tolerated dose (MTD) [ Time Frame: Day 1 to 28 (Cycle 1) ] [ Designated as safety issue: Yes ]
  • Adverse Events as a measure of Safety and Tolerability [ Time Frame: Up to 24 months after first dose ] [ Designated as safety issue: Yes ]
  • Profile of Single Dose and Steady State Pharmacokinetics [ Time Frame: Day 1: pre-dose, 0.5, 1, 2, 4, 6, 8, and 24 hours after the first dose; pre-dose on days 8, 15 and 22; Day 29: pre-dose, 0 .5, 1, 2, 4, 6, 8, 24, 48 hours after first dose, and Cycle 3, Day 1 pre-dose sample ] [ Designated as safety issue: Yes ]
    Cmax, Tmax, AUC, half-life


Estimated Enrollment: 175
Study Start Date: September 2011
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: AP26113

Part 1: Dose Escalation Cohort:

Starting at 30mg of oral AP26113 administered daily, serial cohorts of 3-6 patients will be enrolled and monitored for safety and dose limiting toxicities. Dose levels will increase to 60mg, 90mg, 120mg and beyond depending on the safety findings of previous cohort.

Part 2: Expansion Cohorts:

Patients in the five expansion cohorts (defined below in the eligibility section) will receive the recommended phase 2 dose (RP2D) determined from the outcome of the dose escalation phase (Part 1).

Drug: AP26113
30 mg tablet(s) taken orally and increasing in increments until the maximum tolerated dose (MTD) is identified

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01449461

Locations
United States, California
University of California, San Diego: Moores Cancer Center, Site #099 Recruiting
San Diego, California, United States, 92093
Contact: Dr. Lyudmila Bazhenova       lbazhenova@ucsd.edu   
United States, Colorado
University of Colorado Hospital, Site #015 Recruiting
Aurora, Colorado, United States, 80045
Contact: Sharon Hecker    720-848-0667    Sharon.hecker@ucdenver.edu   
United States, Connecticut
Yale University, Site #033 Recruiting
New Haven, Connecticut, United States, 06520
Contact: Elin Rowen    203-737-3630    elin.rowen@yale.edu   
United States, Illinois
University of Chicago Medical Center, Site #001 Recruiting
Chicago, Illinois, United States, 60637
Contact: Livia Szeto    773-834-0783    lszeto@medicine.bsd.uchicago.edu   
United States, Massachusetts
Mass General Hospital (MGH), Site #047 Recruiting
Boston, Massachusetts, United States, 02114
Contact: Dr. Alice Shaw       ASHAW1@PARTNERS.ORG   
United States, Ohio
The Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Bo Chao, M.D., M.S.    614-293-9424      
Contact: Jeremy Taylor    614-366-0542      
Principal Investigator: Bo Chao, M.D., M.S.         
United States, Pennsylvania
University of Pennsylvania, Site #013 Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Nik Dyanick    215-662-2847    Nikolas.Dyanick@uphs.upenn.edu   
United States, Texas
The University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030-4009
Contact: Kathryn Gold, M.D.    713-792-6110    KAGold@mdanderson.org   
Principal Investigator: Kathryn Gold, M.D.         
Spain
Hospital Germans Trias I Pujol Recruiting
Barcelona, Spain
Contact: Rafael Rosell    +34 93 497 87 29      
Principal Investigator: Rafael Rosell, MD         
Sponsors and Collaborators
Ariad Pharmaceuticals
  More Information

No publications provided by Ariad Pharmaceuticals

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Ariad Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01449461     History of Changes
Other Study ID Numbers: AP26113-11-101
Study First Received: September 30, 2011
Last Updated: April 11, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Ariad Pharmaceuticals:
Advanced Malignancies
Carcinoma, Non-Small-Cell Lung
Anaplastic Large Cell Lymphoma
Diffuse Large Cell Lymphoma
Inflammatory Myofibroblastic Tumors
Anaplastic Lymphoma Kinase (ALK)
Epidermal Growth Factor Receptor (EGFR)
Advanced Cancers
AP26113

Additional relevant MeSH terms:
Neoplasms
Carcinoma
Carcinoma, Non-Small-Cell Lung
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Large-Cell, Anaplastic
Granuloma, Plasma Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, B-Cell
Lymphoma, T-Cell
Granuloma
Pathologic Processes

ClinicalTrials.gov processed this record on July 20, 2014