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Trial record 1 of 1 for:    astx660
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Phase 1-2 Study of ASTX660 in Subjects With Advanced Solid Tumors and Lymphomas

This study is currently recruiting participants.
Verified August 2017 by Astex Pharmaceuticals
Sponsor:
ClinicalTrials.gov Identifier:
NCT02503423
First Posted: July 21, 2015
Last Update Posted: August 24, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Astex Pharmaceuticals
  Purpose
This is an open-label, dose-escalation Phase 1/2 study to assess the safety of ASTX660, determine the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and recommended dosing regimen, and to obtain preliminary efficacy, pharmacokinetic (PK), and target engagement data, in subjects with advanced solid tumors or lymphoma for whom standard life-prolonging measures are not available.

Condition Intervention Phase
Solid Tumors Lymphoma Drug: ASTX660 Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1-2 Study of the Safety, Pharmacokinetics, and Preliminary Activity of ASTX660 in Subjects With Advanced Solid Tumors and Lymphomas

Resource links provided by NLM:


Further study details as provided by Astex Pharmaceuticals:

Primary Outcome Measures:
  • Safety (Phase 1) - number of subjects with AEs, DLTs, abnormal clinical laboratory values or physical exam results [ Time Frame: DLTs will be assessed during cycle 1 (28 days). AEs and other safety indicators will be assessed until 30 days after the last dose of study treatment. It is anticipated that subject may be on study for 2-3 cycles with outliers ]
    Incidence of dose-limiting toxicities (DLTs) and other adverse events (AEs)

  • Efficacy (Phase 2) - radiographic evaluation of tumor size using RECIST 1.1 criteria or another appropriate method if disease is not measureable using RECIST criteria [ Time Frame: It is anticipated that subject may be on study for 2-3 cycles with outliers ]
    Antitumor activity by objective response rate and disease control rate


Secondary Outcome Measures:
  • PK profile - derived from measurement of study drug concentration in serial plasma samples over time [ Time Frame: First 9 weeks of study treatment ]
    Assessment of standard PK parameters: including area under the concentration-time curve (AUC), maximum concentration (Cmax), minimum concentration (Cmin), time to maximum concentration (Tmax), elimination half life (t½), and other secondary PK parameters of ASTX660 if data permit; analysis of ASTX660 metabolites if applicable.

  • Efficacy - radiographic evaluation of tumor size using RECIST 1.1 criteria or another appropriate method if disease is not measureable using RECIST criteria [ Time Frame: It is anticipated that subject may be on study for 2-3 cycles with outliers ]
    Duration of antitumor response and progression-free survival (PFS)

  • Assessment of target (cIAP1) engagement [ Time Frame: It is anticipated that subject may be on study for 2-3 cycles with outliers ]
    Percentage degradation of cIAP1 protein in PBMCs from baseline, in response to ASTX660 treatment.


Estimated Enrollment: 200
Study Start Date: July 2015
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase 1 - Part 1
Dose-escalation stage to identify the MTD and the RP2D, defined as either the MTD or a dose below the MTD that the Data and Safety Review Committee (DSRC) agree shows adequate pharmacological evidence of target engagement and/or clinical activity. Subjects will receive ASTX660 once a day for 7 consecutive days every other week of each 28-day cycle (ie, [7 days on/ 7 days off] ×2; daily dosing on Days 1-7 and 15-21). The starting dose will be escalated stepwise in successive cohorts of 3 to 6 evaluable subjects each (standard 3+3 study design), until the RP2D is determined.
Drug: ASTX660
described above
Experimental: Phase 1 - Part 2
Dose-expansion stage to confirm tolerability of ASTX660 at the RP2D using the every-other-week daily dosing regimen. Up to a total of 12 subjects (including the 3 or 6 subjects treated at the RP2D in Part 1) will be treated at the RP2D.
Drug: ASTX660
described above
Experimental: Phase 1 - Part 3 (optional)
The purpose of the optional Part 3 is to allow for exploration of an alternative dosing regimen of ASTX660 based on emerging safety, PK, and PD data from Parts 1 and 2 (using the original every-other-week dosing regimen), with agreement of the DSRC. If Part 3 is conducted, the plan is to enroll up to 18 evaluable subjects in 1 or more cohorts using a standard 3+3 study design.
Drug: ASTX660
described above
Experimental: Phase 2 - Cohort 1
Treatment with ASTX660 for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) not responsive or relapsed after standard therapy.
Drug: ASTX660
described above
Experimental: Phase 2 - Cohort 2
Treatment with ASTX660 for relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
Drug: ASTX660
described above
Experimental: Phase 2 - Cohort 3
Treatment with ASTX660 for progressive or relapsed peripheral T-cell lymphoma (PTCL).
Drug: ASTX660
described above
Experimental: Phase 2 - Cohort 4
Treatment with ASTX660 for relapsed or refractory cutaneous T-cell lymphoma (CTCL).
Drug: ASTX660
described above
Experimental: Phase 2 - Cohort 5
Treatment with ASTX660 for other tumor types that are characterized by a molecular feature that may confer sensitivity to ASTX660 (eg, oncogenic activation of the NF-κB pathway or documented amplification of the gene loci encoding c-IAP1 or c-IAP2), pending confirmation in writing by the Astex medical monitor.
Drug: ASTX660
described above
Experimental: Phase 2 - Cohort 6
Cervical carcinoma not responsive or relapsed after standard therapy.
Drug: ASTX660
described above

Detailed Description:

ASTX660 is a synthetic small molecule dual antagonist of cellular inhibitor of apoptosis protein (cIAP) 1 and X-linked inhibitor of apoptosis protein (XIAP) that has been shown to have potent proapoptotic and tumor growth inhibitory activity in nonclinical models. ASTX660 has not been previously evaluated in human subjects. The Phase 1 portion of the study will determine the MTD, RP2D, and recommended dosing regimen. The Phase 2 portion will evaluate activity in selected tumor types.

Subjects will continue to receive their assigned treatment throughout the study until the occurrence of disease progression, death, or unacceptable treatment-related toxicity, or until the study is closed by the sponsor.

Tolerability and safety of study treatment will be evaluated throughout the study by collection of clinical and laboratory data. In Phase 2, antitumor response will be assessed according to standard Response Evaluation Criteria in Solid Tumors (RECIST v1.1) using computed tomography (CT) or magnetic resonance imaging (MRI) scans or assessed using another reliable method of disease evaluation appropriate for the tumor type.

  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Able to understand and comply with the protocol and study procedures, understand the risks involved in the study, and provide written informed consent before any study-specific procedure is performed.
  2. Men and women 18 years of age or older.
  3. Subjects with histologically or cytologically confirmed advanced solid tumors or lymphoma that is metastatic or unresectable, and for whom standard life-prolonging measures are not available. Specific tumor types that will be selected for study in Phase 2 are detailed in the protocol.
  4. In the Phase 2 portion of the protocol only, subjects must have measurable disease according to RECIST v1.1, or evaluable disease that can be reliably and consistently followed.
  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
  6. Acceptable organ function, as evidenced by the following laboratory data:

    1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2.0 * upper limit of normal (ULN).
    2. Total serum bilirubin <=1.5 * ULN
    3. Absolute neutrophil count (ANC):

      • Phase 1 and 2 (except Phase 2 subjects with known lymphoma) >=1500 cells/mm3
      • Phase 2 subjects with known lymphoma: >=1000 cells/mm3 (>750 cell/mm3 for subjects with lymphoma in bone marrow)
    4. Platelet count:

      • Phase 1 and 2 (except Phase 2 subject with known lymphoma) >=100,000 cells/mm3
      • Phase 2 subjects with known lymphoma: >= 50,000 cells/mm3; >=25,000 cells/mm3 for subjects with lymphoma in bone marrow
    5. Serum creatinine levels <= 1.5 * ULN, or calculated (by Cockcroft-Gault formula or other accepted formula) or measure creatinine clearance >=50 mL/min.
  7. Women of child-bearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of child-bearing potential and all men with female partners of child-bearing potential must be practicing 2 medically acceptable methods of birth control and must not become pregnant or father a child while receiving treatment with study drug and for at least 3 months after completing treatment.

Exclusion Criteria:

  1. Hypersensitivity to ASTX660, excipients of the drug product, or other components of the study treatment regimen.
  2. Poor medical risk because of systemic diseases (e.g. active uncontrolled infections) in addition to the qualifying disease under study.
  3. Life-threatening illness, significant organ system dysfunction, or other condition that, in the investigator's opinion, could compromise subject safety or the integrity of the study outcomes, or interfere with the absorption or metabolism of ASTX660.
  4. History of, or at risk for, cardiac disease, as evidenced by 1 or more of the following conditions:

    1. Abnormal left ventricular ejection fraction (LVEF; <50%) or echocardiogram ECHO or multiple gated acquisition scan (MUGA). [Applies to Phase 1 only; ECHO/MUGA scans are not performed in Phase 2.]
    2. Congestive cardiac failure of >= Grade 3 severity according to New York Heart Association (NYHA) functional classification defined as subjects with marked limitation of activity and who are comfortable only at rest.
    3. Unstable cardiac disease including angina or hypertension as defined by the need for overnight hospital admission within the last 3 months (90 days).
    4. History or presence of complete left bundle branch block, heart block, cardiac pacemaker or significant arrhythmia.
    5. Concurrent treatment with any medical that prolongs QT interval and may induce torsades de pointes, and which cannot be discontinued at least 2 weeks before treatment with ASTX660. [Applies to Phase 1 only].
    6. Personal history of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy.
    7. Screening 12-lead ECG with measurable QTc interval (according to either Fridericia's or Bazett's correction) of >=470 msec).
  5. Known history of human immunodeficiency virus (HIV) infection, or seropositive results consistent with active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection.
  6. Grade 2 or greater neuropathy. [Applies to Phase 1 only].
  7. Known brain metastases, unless stable or previously treated.
  8. Known significant mental illness or other conditions such as active alcohol or other substance abuse that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol treatment or assessments.
  9. Prior anticancer treatments or therapies within the indicated time window prior to first dose of study treatment (ASTX660), as follows:

    • Cytotoxic chemotherapy or radiotherapy within 3 weeks prior and any encountered treatment-related toxicities (excepting alopecia) not resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2].
    • Monoclonal antibodies within 4 weeks prior and any encountered treatment-related toxicities not resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2].
    • Investigational drugs (small molecules or biologics) within the longer of 2 weeks or 5 half-lives prior to study treatment and any encountered treatment-related toxicities not resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2].
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02503423


Contacts
Contact: Purvee Kumar +1-925-560-2863 Purvee.kumar@astx.com
Contact: Jessica Nario +1-925-560-2931 Jessica.Nario@astx.com

Locations
United States, Arizona
Pinnacle Oncology Recruiting
Scottsdale, Arizona, United States, 852558
United States, California
Cedars-Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048
United States, Connecticut
Simlow Cancer Hospital at Yale Recruiting
New Haven, Connecticut, United States, 06510
United States, Texas
Start - Ids Recruiting
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
Astex Pharmaceuticals
Investigators
Study Director: Edwin Rock, MD, PhD Astex Pharmaceuticals
  More Information

Responsible Party: Astex Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02503423     History of Changes
Other Study ID Numbers: ASTX660-01
First Submitted: July 2, 2015
First Posted: July 21, 2015
Last Update Posted: August 24, 2017
Last Verified: August 2017

Additional relevant MeSH terms:
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases


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