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

Lymphoma Clinical Trial

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 Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02503423
• Other study ID #: ASTX660-01
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: July 2015
• Est. completion date: October 2024

Study information

• Verified date: May 2024
• Source: Astex Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 230
• Est. completion date: October 2024
• Est. primary completion date: October 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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].

Related Conditions & MeSH terms

• Lymphoma
• Solid Tumors

Intervention

Drug:
• ASTX660
described above

Locations

Country	Name	City	State
Belgium	Intitut Jules Boredt	Bruxelles
Belgium	Universitair Ziekenhuis Gent	Gent	Oost-Vlaanderen
Belgium	Centre Hospitalier Universitaire Universite Catholique de Louvain - Site Godinne	Yvoir	Namur
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	Nova Scotia Health Athority-Qeii HSC	Halifax	Nova Scotia
Canada	Jewish General Hospital	Montréal	Quebec
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
Canada	Sunnybrook Hospital	Toronto	Ontario
Canada	British Columbia Cancer Agency	Vancouver	British Columbia
Canada	Cancer Care Manitoba	Winnipeg	Manitoba
France	Institut Bergonié, Unicancer	Bordeaux
France	Centre Antoine Lacassagne, Oncologie Médicale	Nice
France	Centre Hospitalier Lyon Sud	Pierre-Bénite	Lyon
France	Centre Henri Becquerel, Hematology	Rouen
France	Institut Universitaire du Cancer - Oncopôle, Department d'Hématologie	Toulouse Cedex 9
France	CRU de Tours - Hôpital Bretonneau, Hématologie -Thérapy Cellulaire	Tours
France	Gustave Roussy Cancer Campus (IGR)	Villejuif	Cedex
Hungary	Semmelweis Egyetem - I. sz. Belgyógyászati Klinika	Budapest
Hungary	Debreceni Egyetem Klinikai Központ	Debrecen
Hungary	Szabolcs-Szatmár-Bereg Megyei Kórházak És Egyetemi Oktatókórház	Nyíregyháza
Italy	Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi	Bologna
Italy	Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia	Brescia
Italy	Instituto Europeo di Oncologia	Milan
Italy	Azienda Socio Santaria Territoriale Monza- Osperdale San Gerado	Monza
Spain	Institut Catala d'Oncologia	Girona	Giona
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Fundacion Jimenez Diaz Preview	Madrid
Spain	imCORE - Clínica Universidad de Navarra	Pamplona	Navarra
United Kingdom	University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital	Birmingham
United Kingdom	Beatson Cancer Center and University of Glasgow	Glasgow
United Kingdom	University Hospitals of Leicester NHS Trust	Leicester	East Midlands
United Kingdom	Guy's and Saint Thomas' NHS Foundation Trust	London
United Kingdom	University College London Hospitals NHS Foundation Trust	London
United Kingdom	The Christie NHS Foundation Trust, Christie Hospital	Manchester
United Kingdom	Churchill Hospital, Oxford University Hospital NHS Trust	Oxford	Oxfordshire
United Kingdom	University Hospital Southhampton NHS Foundation Trust - Somers Cancer Research	Southampton	Hampshire
United Kingdom	The Royal Marsden NHS Foundation Trust	Sutton	Surrey
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University winship Cancer Institute	Atlanta	Georgia
United States	The Sidney Kimmel Comprehensive Cancer Center at John Hopkins	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Hollings Cancer Center	Charleston	South Carolina
United States	Robert H. Lurie Comprehensive Cancer Center of Northwestern University	Chicago	Illinois
United States	The Ohio State University and Wexner Medical Center, James Cancer Hospital	Columbus	Ohio
United States	Summit Medical Group - Florham Park Campus/Atlantic Health	Florham Park	New Jersey
United States	CliniCore Texas	Houston	Texas
United States	MD Anderson Cancer Center	Houston	Texas
United States	Dartmouth-Hitchcock Medical Center (DHMC)	Lebanon	New Hampshire
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	USC/Norris Comprehensive Cancer Center	Los Angeles	California
United States	Vanderbilt Ingram Cancer Center	Nashville	Tennessee
United States	Simlow Cancer Hospital at Yale	New Haven	Connecticut
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	New York Presbyterian Hospital Columbia University Medical Center	New York	New York
United States	New York University Langone Medical Center	New York	New York
United States	University of Oklahoma Stephenson Cancer Center	Oklahoma City	Oklahoma
United States	West Penn Hospital	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Virgina Commonwealth University	Richmond	Virginia
United States	Rochester Skin Lymphoma Medical Group	Rochester	New York
United States	UC Davis Medical Center	Sacramento	California
United States	START- South Texas Accelerated Research Therapeutics	San Antonio	Texas
United States	HonorHealth Research Institute	Scottsdale	Arizona
United States	University of Washington, Seattle Cancer Care Alliance	Seattle	Washington
United States	Wake Forest Baptist Health	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Astex Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  France,  Hungary,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety (Phase 1) - number of subjects with AEs, DLTs, abnormal clinical laboratory values or physical exam results	Incidence of dose-limiting toxicities (DLTs) and other adverse events (AEs)	Up to 78 months
Primary	Efficacy (Phase 2) - antitumor activity assessed by objective response rate (ORR)	Antitumor activity by objective response rate	Up to 84 months
Primary	Efficacy (Phase 2) - antitumor activity assessed by disease control rate (DCR)	Antitumor activity by disease control rate	Up to 84 months
Secondary	Pharmacokinetic outcome of concentration-time curve (AUC)	Assessment of pharmacokinetic parameter area under the concentration-time curve (AUC).	First 9 weeks of study treatment
Secondary	Pharmacokinetic outcome of maximum concentration (Cmax)	Assessment of pharmacokinetic parameter maximum concentration (Cmax).	First 9 weeks of study treatment
Secondary	Pharmacokinetic outcome of minimum concentration (Cmin)	Assessment of pharmacokinetic parameter minimum concentration (Cmin).	First 9 weeks of study treatment
Secondary	Pharmacokinetic outcome of time to maximum concentration (Tmax)	Assessment of pharmacokinetic parameter time to maximum concentration (Tmax)	First 9 weeks of study treatment
Secondary	Pharmacokinetic outcome of samples over time	Assessment of pharmacokinetic parameter elimination half life (t½).	First 9 weeks of study treatment
Secondary	Pharmacokinetic outcome of samples over time	Assessment of pharmacokinetic parameter of other secondary PK parameters of ASTX660 if data permit.	First 9 weeks of study treatment
Secondary	Pharmacokinetic outcome of analysis of ASTX660 metabolites if applicable	Assessment of pharmacokinetic parameter analysis of ASTX660 metabolites if applicable.	First 9 weeks of study treatment
Secondary	Duration of antitumor response	Time from the date of the earliest assessment of complete response or partial response to the date of relapse or death, whichever occurs earlier, or the last efficacy assessment date for subjects without a relapse or death.	Up to 84 months
Secondary	Progression-free survival	Number of days from the start of the study treatment to disease progression or death, whichever occurs first.	Up to 84 months
Secondary	Overall survival	Number of days from the day the subject received the first study treatment to the date of death, regardless of cause.	Up to 84 months
Secondary	Assessment of target (cIAP1) engagement	Percentage degradation of cIAP1 protein in PBMCs from baseline, in response to ASTX660 treatment.	Up to 84 months