Clinical trial NCT02503423: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Solid Tumors
Lymphoma
Keywords: cervical cancer
HNSCC
CTCL
PTCL
DLBCL
Lead sponsor: Taiho Oncology, Inc.
Sponsor class: INDUSTRY
First posted: 2015-07-21
Enrollment: 230
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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. The Phase 1 portion of the study (completed) 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.

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, provided that brentuximab vedotin is locally approved and available.
   2. 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 for 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:

   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; ie, not applicable for Cohorts 3 or 4) \>=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; ie, not applicable for Cohorts 3 or 4) \>=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.
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).
   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).
   8. 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:

   1. 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 \[Phase 2\].
   2. Skin directed treatments, including topicals and radiation within 2 weeks prior.
   3. 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 \[Phase 2\].
   4. Small molecules or biologics (investigational or approved) 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 \[Phase 2\].
   5. 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.
10. Concurrent second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy or superficial bladder cancer \[Phase 2\].
11. Known central nervous system (CNS) lymphoma \[Phase 2\].
12. Patients with a history of allogenic transplant must not have ≥Grade 3 graft-versus-host disease (GVHD) or any clinically significant GVHD requiring systemic immunosuppression \[Phase 2\].
13. Systemic corticosteroids \>20 mg prednisone equivalent (unless patient has been taking a continuous dose for \>3 weeks prior to study entry and there is documented radiological progression) \[Phase 2\]. Stable dose of medium or low potency topical corticosteroids for at least 3 weeks prior to study entry are permitted \[Phase 2\].

Primary outcomes:
measure: Safety (Phase 1) - number of subjects with AEs, DLTs, abnormal clinical laboratory values or physical exam results
timeFrame: Up to 78 months
measure: Efficacy (Phase 2) - antitumor activity assessed by objective response rate (ORR)
timeFrame: Up to 84 months
measure: Efficacy (Phase 2) - antitumor activity assessed by disease control rate (DCR)
timeFrame: Up to 84 months
Secondary outcomes:
measure: Pharmacokinetic outcome of concentration-time curve (AUC)
timeFrame: First 9 weeks of study treatment
measure: Pharmacokinetic outcome of maximum concentration (Cmax)
timeFrame: First 9 weeks of study treatment
measure: Pharmacokinetic outcome of minimum concentration (Cmin)
timeFrame: First 9 weeks of study treatment
measure: Pharmacokinetic outcome of time to maximum concentration (Tmax)
timeFrame: First 9 weeks of study treatment
measure: Pharmacokinetic outcome of samples over time
timeFrame: First 9 weeks of study treatment
measure: Pharmacokinetic outcome of samples over time
timeFrame: First 9 weeks of study treatment
measure: Pharmacokinetic outcome of analysis of ASTX660 metabolites if applicable
timeFrame: First 9 weeks of study treatment
measure: Duration of antitumor response
timeFrame: Up to 84 months
measure: Progression-free survival
timeFrame: Up to 84 months
measure: Overall survival
timeFrame: Up to 84 months
measure: Assessment of target (cIAP1) engagement
timeFrame: Up to 84 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Scottsdale
country: United States
facility: HonorHealth Research Institute
state: Arizona
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: New Haven
country: United States
facility: Simlow Cancer Hospital at Yale
state: Connecticut
city: Atlanta
country: United States
facility: Emory University winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
state: Illinois
city: Baltimore
country: United States
facility: The Sidney Kimmel Comprehensive Cancer Center at John Hopkins
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center (DHMC)
state: New Hampshire
city: Florham Park
country: United States
facility: Summit Medical Group - Florham Park Campus/Atlantic Health
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: New York University Langone Medical Center
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Rochester
country: United States
facility: Rochester Skin Lymphoma Medical Group
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University and Wexner Medical Center, James Cancer Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Stephenson Cancer Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Pittsburgh
country: United States
facility: West Penn Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Hollings Cancer Center
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt Ingram Cancer Center
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: CliniCore Texas
state: Texas
city: San Antonio
country: United States
facility: START- South Texas Accelerated Research Therapeutics
state: Texas
city: Richmond
country: United States
facility: Virgina Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: University of Washington, Seattle Cancer Care Alliance
state: Washington
city: Yvoir
country: Belgium
facility: Centre Hospitalier Universitaire Universite Catholique de Louvain - Site Godinne
state: Namur
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
state: Oost-Vlaanderen
city: Bruxelles
country: Belgium
facility: Intitut Jules Boredt
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Cancer Agency
state: British Columbia
city: Winnipeg
country: Canada
facility: Cancer Care Manitoba
state: Manitoba
city: Halifax
country: Canada
facility: Nova Scotia Health Athority-Qeii HSC
state: Nova Scotia
city: Toronto
country: Canada
facility: Sunnybrook Hospital
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Villejuif
country: France
facility: Gustave Roussy Cancer Campus (IGR)
state: Cedex
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon Sud
state: Lyon
city: Bordeaux
country: France
facility: Institut Bergonié, Unicancer
city: Nice
country: France
facility: Centre Antoine Lacassagne, Oncologie Médicale
city: Rouen
country: France
facility: Centre Henri Becquerel, Hematology
city: Toulouse Cedex 9
country: France
facility: Institut Universitaire du Cancer - Oncopôle, Department d'Hématologie
city: Tours
country: France
facility: CRU de Tours - Hôpital Bretonneau, Hématologie -Thérapy Cellulaire
city: Budapest
country: Hungary
facility: Semmelweis Egyetem - I. sz. Belgyógyászati Klinika
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Központ
city: Nyíregyháza
country: Hungary
facility: Szabolcs-Szatmár-Bereg Megyei Kórházak És Egyetemi Oktatókórház
city: Bologna
country: Italy
facility: Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi
city: Brescia
country: Italy
facility: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
city: Milan
country: Italy
facility: Instituto Europeo di Oncologia
city: Monza
country: Italy
facility: Azienda Socio Santaria Territoriale Monza- Osperdale San Gerado
city: Girona
country: Spain
facility: Institut Catala d'Oncologia
state: Giona
city: Pamplona
country: Spain
facility: imCORE - Clínica Universidad de Navarra
state: Navarra
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Jimenez Diaz Preview
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester NHS Trust
state: East Midlands
city: Southampton
country: United Kingdom
facility: University Hospital Southhampton NHS Foundation Trust - Somers Cancer Research
state: Hampshire
city: Oxford
country: United Kingdom
facility: Churchill Hospital, Oxford University Hospital NHS Trust
state: Oxfordshire
city: Sutton
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
state: Surrey
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital
city: Glasgow
country: United Kingdom
facility: Beatson Cancer Center and University of Glasgow
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: Guy's and Saint Thomas' NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust, Christie Hospital
Study officials:
References:
citation: Johnson CN, Ahn JS, Buck IM, Chiarparin E, Day JEH, Hopkins A, Howard S, Lewis EJ, Martins V, Millemaggi A, Munck JM, Page LW, Peakman T, Reader M, Rich SJ, Saxty G, Smyth T, Thompson NT, Ward GA, Williams PA, Wilsher NE, Chessari G. A Fragment-Derived Clinical Candidate for Antagonism of X-Linked and Cellular Inhibitor of Apoptosis Proteins: 1-(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2 H,3 H-pyrrolo[3,2- b]pyridin-1-yl)-2-[(2 R,5 R)-5-methyl-2-([(3R)-3-methylmorpholin-4-yl]methyl)piperazin-1-yl]ethan-1-one (ASTX660). J Med Chem. 2018 Aug 23;61(16):7314-7329. doi: 10.1021/acs.jmedchem.8b00900. Epub 2018 Aug 9.