Advanced Solid Tumors and Lymphomas that are metastatic or unresectable: cohort 1:Recurrent/metastatic head and neck squamous cell carcinoma
Conditions
Interventions
Product Code: ASTX660
Pharmaceutical Form: Capsule
INN or Proposed INN: ASTX660
CAS Number: 1799328-87-2
Current Sponsor code: ASTX660
Concentration unit: mg milligram(s)
Concentration type: equal
Con
Sponsors
Astex Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Subjects must fulfill all of the following 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. 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, subjects must have evidence of documented progressive disease and must have received at least two prior systemic therapies [Phase 2 Cohort 3 and 4]. a) Subjects with CD30-positive lymphoma must have received, be ineligible for, or intolerant to brentuximab vedotin, provided that brentuximab vedotin is locally approved and available. b) Subjects with mycosis fungoides or Sezary syndrome must have received, be ineligible, or intolerant to mogamulizumab, provided that mogamulizumab is locally approved and available. 5. In the Phase 2 portion of the protocol only, subjects must have measurable disease according to response criteria appropriate to their type of cancer. a) For Phase 2 Cohort 3 (PTCL), measurable disease by contrast-enhanced diagnostic CT (at least 1 nodal lesion >1.5 cm or extranodal lesions >1.0 cm) is required. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 7. Acceptable organ function, as evidenced by the following laboratory data: a. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =2.0 × upper limit of normal (ULN). b. Total serum bilirubin =1.5 × ULN. c. Absolute neutrophil count (ANC): o Phase 1 and 2 (except subjects with known lymphoma [ie, Not applicable for Cohorts 3 or 4]): =1500 cells/mm3. o Phase 2 subjects with known lymphoma: =1000 cells/mm3 (=750 cells/mm3 for subjects with lymphoma in bone marrow) (Administration of myeloid growth factors within 14 days prior to study entry are not allowed). d. Platelet count: o Phase 1 and 2 (except subjects with known lymphoma [ie, Not applicable for Cohorts 3 or 4]): =100,000 cells/mm3. o Phase 2 subjects with known lymphoma: =50,000 cells/mm3 (=25,000 cells/mm3 for subjects with lymphoma in bone marrow) (transfusion within 21 days prior to study entry are not allowed). e. Serum creatinine levels =1.5 × ULN, or calculated (by Cockcroft-Gault formula or other accepted formula) or measured creatinine clearance =50 mL/min. f. Amylase and lipase =ULN. [Applies to Phase 2]. 8. Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG]; must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women
Exclusion criteria
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 (eg, 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: a) Abnormal left ventricular ejection fraction (LVEF; <50%) on echocardiogram (ECHO) or multiplegated acquisition scan (MUGA). [Applies to both Phase 1 and Phase 2]. b) 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. c) Unstable cardiac disease including unstable angina or hypertension as defined by the need for overnight hospital admission within the last 3 months (90 days). d) History or presence of complete left bundle branch block, third-degree heart block, cardiac pacemaker or clinically significant arrhythmia. e) Concurrent treatment with any medication 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.] f) Personal history of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy. g) 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: a) Cytotoxic chemotherapy or radiotherapy within 3 weeks prior (6 weeks if nitrosoureas). Palliative radiotherapy to a single lesion within 2 weeks prior. Any encountered treatment-related toxicities (excepting alopecia) must be stabilized or resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2]. b) Skin directed treatments, including topicals and radiation within 2 weeks prior. c) Monoclonal antibodies within 4 weeks prior. Any encountered treatment-related toxicities must be stabilized or resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2]. d) At least 6 weeks must have elapsed since CAR-T infusion and subjects must have experienced disease progression, and not have residual circulating CAR-T cells in peripheral blood (based on local assessment). Any encountered treatment-related toxicities must have resolved to Grade =1 e) Small molecules or
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • Phase 1: To assess safety, and to identify the maximum tolerated dose (MTD), the recommended Phase 2 dose (RP2D), and the recommended dosing regimen of ASTX660(Completed). • Phase 2: To assess preliminary efficacy, as determined by response rate in certain tumor types.;Secondary Objective: • To determine the pharmacokinetic (PK) parameters of orally administered ASTX660 in humans. • To evaluate other efficacy parameters, such as duration of response (DOR) and progression-free survival (PFS). • To evaluate relevant pharmacodynamic (PD) targets and potential biomarkers of ASTX660 activity.;Primary end point(s): Primary Endpoint(s) Phase 1 (Completed): Incidence of DLTs and other adverse events (AEs) to determine the MTD, RP2D, and recommended dosing regimen of ASTX660. Phase 2: Antitumor activity assessed by objective response rate (ORR) and disease control rate (DCR) as assessed by the investigator using the following criteria: o Cohort 1, 5, and 6: RECIST 1.1 criteria o Cohort 2: 2014 Lugano Classification o Cohort 3: 2014 Lugano Classification and LYRIC criteria o Cohort 4: Global Response Score (skin, blood and node using Olsen classification and viscera using Lugano and LYRIC criteria).;Timepoint(s) of evaluation of this end point: Safety will be monitored at each study visit by recording of AEs, SAEs, DLTs, and concomitant medications; additional assessments that may be performed at selected visits include complete or symptom-directed physical examinations, recording of weight and height, vital signs, ECOG performance status, 12-lead ECGs, and clinical laboratory tests. Phase 1: echocardiogram (ECHO)/multiple-gated acquisition scans will be performed. Phase 2: Every 2 months for the first 6 months (6 cycles), and then every 3 months hereafter until clinical and/or radiographic disease progression, or death, or the subject withdraws consent | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Endpoint(s) 1. PK parameters of ASTX660, 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. 2. DOR, PFS and overall survival. 3. Percentage degradation of cIAP1 protein in PBMCs from baseline, in response to ASTX660 treatment [applies to Phase 1 only]. 4. Antitumor activity (ORR, DOR, and PFS) based on independent review committee (IRC) assessment: Phase 2 Cohort 3 Expansion using 2014 Lugano Classification with LYRIC criteria, and Phase 2 Cohort 4 Expansion using Global Response Score (skin, blood and node using Olsen classification and viscera using Lugano classification with LYRIC criteria). 5. Antitumor activity (DOR and PFS) based on investigator assessment using the Lugano classification with LYRIC criteria (Phase 2 Cohort 3 Expansion), and Phase 2 Cohort 4 Expansion using Global Response Score (skin, blood and node using Olsen classification and viscera using Lugano classification with LYRIC criteria). 6. Antitumor activity (ORR, DOR, and PFS) based on IRC assessment using the Lugano classification alone (Phase 2 Cohort 3 Expansion).;Timepoint(s) of evaluation of this end point: 1.At specified study visits, blood samples for PK will be collected predose for assessment of ASTX660 concentration in plasma. In addition, serial samples will be collected predose and at several specified time points after dosing on C1D1, C1D7, C2D1, and C2D7. Additionally, in Phase 2 for Cohorts 3 [PTCL] and 4 [CTCL], blood will be collected for PK analysis in Cycle 1 only. 2.Every 2 months for the first 6 months (6 cycles), and then every 3 months hereafter until clinical and/or radiographic disease progression, or death, or the subject withdraws consent 3. Blood samples will be collected at screening | — |
Countries
Belgium, Canada, France, Hungary, Italy, Spain, United Kingdom, United States
Contacts
Public ContactASTX660-01 Clinical Team
Astex Pharmaceuticals, Inc
Outcome results
None listed