Clinical Trials /

Phase 1-2 Study of ASTX660 in Subjects With Advanced Solid Tumors and Lymphomas

NCT02503423

Description:

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.

Related Conditions:
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase 1-2 Study of ASTX660 in Subjects With Advanced Solid Tumors and Lymphomas
  • Official Title: Phase 1-2 Study of the Safety, Pharmacokinetics, and Preliminary Activity of ASTX660 in Subjects With Advanced Solid Tumors and Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: ASTX660-01
  • NCT ID: NCT02503423

Conditions

  • Solid Tumors
  • Lymphoma

Interventions

DrugSynonymsArms
ASTX660Treatment of ASTX660 for advanced solid tumors and lymphomasPhase 1 - Part 1

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.

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
      using computed tomography (CT) or magnetic resonance imaging (MRI) scans or other appropriate
      disease evaluation methods. In subjects with solid tumors, response will be evaluated
      according to standard Response Evaluation Criteria in Solid Tumors (RECIST v1.1; Appendix 3).
      In subjects with DLBCL and PTCL, antitumor response will be evaluated according to the 2014
      Lugano classification (Appendix 5). In subjects with CTCL, global overall response criteria
      will be used, based on skin, blood, node, and viscera assessments (Appendix 4).
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1 - Part 1ExperimentalDose-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.
  • ASTX660
Phase 1 - Part 2ExperimentalDose-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.
  • ASTX660
Phase 1 - Part 3 (optional)ExperimentalThe 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.
  • ASTX660
Phase 2 - Cohort 1ExperimentalTreatment with ASTX660 for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) not responsive or relapsed after standard therapy.
  • ASTX660
Phase 2 - Cohort 2ExperimentalTreatment with ASTX660 for relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
  • ASTX660
Phase 2 - Cohort 3ExperimentalTreatment with ASTX660 for progressive or relapsed peripheral T-cell lymphoma (PTCL).
  • ASTX660
Phase 2 - Cohort 4ExperimentalTreatment with ASTX660 for relapsed or refractory cutaneous T-cell lymphoma (CTCL).
  • ASTX660
Phase 2 - Cohort 5ExperimentalTreatment 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.
  • ASTX660
Phase 2 - Cohort 6ExperimentalTreatment with ASTX660 for cervical carcinoma not responsive or relapsed after standard therapy.
  • ASTX660

Eligibility 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.

             a) For Phase 2 Cohort 3, subjects must have histologically confirmed PTCL (local
             pathology report) as defined by 2016 World Health Organization (WHO) classification.
             The following subtypes are eligible for the study: adult T-cell lymphoma/leukemia,
             extranodal natural killer (NK)/T-cell lymphoma nasal type, enteropathy-associated
             T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, hepatosplenic
             T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, peripheral T-cell
             lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, follicular
             T-cell lymphoma, nodal peripheral T-cell with T-follicular helper (THF) phenotype, and
             anaplastic large-cell lymphoma.

          4. For Phase 2 Cohorts 3 and 4, patients must have evidence of documented progressive
             disease and must have received at least two prior systemic therapies.

               1. Subjects with CD30-positive lymphoma must have received, be ineligible for, or
                  intolerant to brentuximab vedotin.

               2. Subjects with mycosis fungoides or Sezary syndrome must have received, be
                  ineligible or intolerant to mogamulizumab.

                  5) In the Phase 2 portion of the protocol only, subjects must have measurable
                  disease according to response criteria appropriate for their type of cancer.

        6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

        7. 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.

          6. Amylase and lipase <=ULN [Applies to Phase 2].

             8. Women of child-bearing potential (according to recommendations of the Clinical
             Trial Facilitation Group [CTFG]; see protocol for details) must not be pregnant or
             breastfeeding and must have a negative pregnancy test at screening. Women of
             child-bearing potential and men with female partners of child-bearing potential must
             agree to practice 2 highly effective contraceptive measures of birth control (as
             described in the protocol) and must agree not to become pregnant or father a child
             while receiving treatment with study drug and for at least 3 months after completing
             treatment. Contraceptive measures which may be considered highly effective comprise
             combined hormonal contraception (oral, vaginal, or transdermal) or progestogen-only
             hormonal contraception (oral, injectable, implantable) associated with inhibition of
             ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal
             occlusion, sexual abstinence, and surgically successful vasectomy. Abstinence is
             acceptable only if it is consistent with the preferred and usual lifestyle of the
             subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation
             methods) and withdrawal are not acceptable methods of birth control.

        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 both Phase 1 and 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).

             h) Any other condition that, in the opinion of the investigator, could put the subject
             at increased cardiac risk.

          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]. Grade 3 or greater neuropathy
             [Applies to Phase 2].

          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].

               -  Skin directed treatments, including topicals and radiation within 2 weeks prior.

               -  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].
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Incidence of dose-limiting toxicities (DLTs) and other adverse events (AEs)

Secondary Outcome Measures

Measure:Pharmacokinetic outcome of concentration-time curve (AUC)
Time Frame:First 9 weeks of study treatment
Safety Issue:
Description:Assessment of pharmacokinetic parameter area under the concentration-time curve (AUC).
Measure:Pharmacokinetic outcome of maximum concentration (Cmax)
Time Frame:First 9 weeks of study treatment
Safety Issue:
Description:Assessment of pharmacokinetic parameter maximum concentration (Cmax).
Measure:Pharmacokinetic outcome of minimum concentration (Cmin)
Time Frame:First 9 weeks of study treatment
Safety Issue:
Description:Assessment of pharmacokinetic parameter minimum concentration (Cmin).
Measure:Pharmacokinetic outcome of time to maximum concentration (Tmax)
Time Frame:First 9 weeks of study treatment
Safety Issue:
Description:Assessment of pharmacokinetic parameter time to maximum concentration (Tmax)
Measure:Pharmacokinetic outcome of samples over time
Time Frame:First 9 weeks of study treatment
Safety Issue:
Description:Assessment of pharmacokinetic parameter elimination half life (t½).
Measure:Pharmacokinetic outcome of samples over time
Time Frame:First 9 weeks of study treatment
Safety Issue:
Description:Assessment of pharmacokinetic parameter of other secondary PK parameters of ASTX660 if data permit.
Measure:Pharmacokinetic outcome of analysis of ASTX660 metabolites if applicable
Time Frame:First 9 weeks of study treatment
Safety Issue:
Description:Assessment of pharmacokinetic parameter analysis of ASTX660 metabolites if applicable.
Measure: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
Safety Issue:
Description:Duration of antitumor response and progression-free survival (PFS)
Measure:Assessment of target (cIAP1) engagement
Time Frame:It is anticipated that subject may be on study for 2-3 cycles with outliers
Safety Issue:
Description:Percentage degradation of cIAP1 protein in PBMCs from baseline, in response to ASTX660 treatment.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Astex Pharmaceuticals

Trial Keywords

  • cervical cancer
  • HNSCC
  • CTCL
  • PTCL
  • DLBCL

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