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

Sponsor

Astex Pharmaceuticals, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02503423

Collaborator

(none)

230

Enrollment

Locations

Arms

Anticipated Duration (Months)

3.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumors Lymphoma	Drug: ASTX660	Phase 1/Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

230 participants

Allocation:

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

Actual Study Start Date :

Jul 1, 2015

Anticipated Primary Completion Date :

May 1, 2023

Anticipated Study Completion Date :

May 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1 - Part 1 (completed) 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 Other Names: Treatment of ASTX660 for advanced solid tumors and lymphomas
Experimental: Phase 1 - Part 2 (completed) 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 Other Names: Treatment of ASTX660 for advanced solid tumors and lymphomas
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 pharmacodynamic (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 Other Names: Treatment of ASTX660 for advanced solid tumors and lymphomas
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 Other Names: Treatment of ASTX660 for advanced solid tumors and lymphomas
Experimental: Phase 2 - Cohort 2 Treatment with ASTX660 for relapsed or refractory diffuse large B-cell lymphoma (DLBCL).	Drug: ASTX660 described above Other Names: Treatment of ASTX660 for advanced solid tumors and lymphomas
Experimental: Phase 2 - Cohort 3 Treatment with ASTX660 for progressive or relapsed peripheral T-cell lymphoma (PTCL).	Drug: ASTX660 described above Other Names: Treatment of ASTX660 for advanced solid tumors and lymphomas
Experimental: Phase 2 - Cohort 4 Treatment with ASTX660 for relapsed or refractory cutaneous T-cell lymphoma (CTCL).	Drug: ASTX660 described above Other Names: Treatment of ASTX660 for advanced solid tumors and lymphomas
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 Other Names: Treatment of ASTX660 for advanced solid tumors and lymphomas
Experimental: Phase 2 - Cohort 6 Treatment with ASTX660 for cervical carcinoma not responsive or relapsed after standard therapy.	Drug: ASTX660 described above Other Names: Treatment of ASTX660 for advanced solid tumors and lymphomas

Outcome Measures

Primary Outcome Measures

Safety (Phase 1) - number of subjects with AEs, DLTs, abnormal clinical laboratory values or physical exam results [Up to 78 months]
Incidence of dose-limiting toxicities (DLTs) and other adverse events (AEs)
Efficacy (Phase 2) - antitumor activity assessed by objective response rate (ORR) [Up to 84 months]
Antitumor activity by objective response rate
Efficacy (Phase 2) - antitumor activity assessed by disease control rate (DCR) [Up to 84 months]
Antitumor activity by disease control rate

Secondary Outcome Measures

Pharmacokinetic outcome of concentration-time curve (AUC) [First 9 weeks of study treatment]
Assessment of pharmacokinetic parameter area under the concentration-time curve (AUC).
Pharmacokinetic outcome of maximum concentration (Cmax) [First 9 weeks of study treatment]
Assessment of pharmacokinetic parameter maximum concentration (Cmax).
Pharmacokinetic outcome of minimum concentration (Cmin) [First 9 weeks of study treatment]
Assessment of pharmacokinetic parameter minimum concentration (Cmin).
Pharmacokinetic outcome of time to maximum concentration (Tmax) [First 9 weeks of study treatment]
Assessment of pharmacokinetic parameter time to maximum concentration (Tmax)
Pharmacokinetic outcome of samples over time [First 9 weeks of study treatment]
Assessment of pharmacokinetic parameter elimination half life (t½).
Pharmacokinetic outcome of samples over time [First 9 weeks of study treatment]
Assessment of pharmacokinetic parameter of other secondary PK parameters of ASTX660 if data permit.
Pharmacokinetic outcome of analysis of ASTX660 metabolites if applicable [First 9 weeks of study treatment]
Assessment of pharmacokinetic parameter analysis of ASTX660 metabolites if applicable.
Duration of antitumor response [Up to 84 months]
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.
Progression-free survival [Up to 84 months]
Number of days from the start of the study treatment to disease progression or death, whichever occurs first.
Overall survival [Up to 84 months]
Number of days from the day the subject received the first study treatment to the date of death, regardless of cause.
Assessment of target (cIAP1) engagement [Up to 84 months]
Percentage degradation of cIAP1 protein in PBMCs from baseline, in response to ASTX660 treatment.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.
Men and women 18 years of age or older.
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.

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.

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.
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.
Subjects with mycosis fungoides or Sezary syndrome must have received, be ineligible or intolerant to mogamulizumab, provided that mogamulizumab is locally approved and available.
In the Phase 2 portion of the protocol only, subjects must have measurable disease according to response criteria appropriate for their type of cancer.

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.

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
Acceptable organ function, as evidenced by the following laboratory data:
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2.0 * upper limit of normal (ULN).
Total serum bilirubin <=1.5 * ULN
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)

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

Serum creatinine levels <= 1.5 * ULN, or calculated (by Cockcroft-Gault formula or other accepted formula) or measure creatinine clearance >=50 mL/min.
Amylase and lipase <=ULN.
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:

Hypersensitivity to ASTX660, excipients of the drug product, or other components of the study treatment regimen.
Poor medical risk because of systemic diseases (e.g. active uncontrolled infections) in addition to the qualifying disease under study.
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.
History of, or at risk for, cardiac disease, as evidenced by 1 or more of the following conditions:
Abnormal left ventricular ejection fraction (LVEF; <50%) or echocardiogram ECHO or multiple gated acquisition scan (MUGA).
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.
Unstable cardiac disease including angina or hypertension as defined by the need for overnight hospital admission within the last 3 months (90 days).
History or presence of complete left bundle branch block, heart block, cardiac pacemaker or significant arrhythmia.
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].
Personal history of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy.
Screening 12-lead ECG with measurable QTc interval (according to either Fridericia's or Bazett's correction) of >=470 msec).
Any other condition that, in the opinion of the investigator, could put the subject at increased cardiac risk.
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.
Grade 2 or greater neuropathy [Applies to Phase 1]. Grade 3 or greater neuropathy [Applies to Phase 2].
Known brain metastases, unless stable or previously treated.
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.
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].
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].
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.
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].
Known central nervous system (CNS) lymphoma [Phase 2].
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].
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].

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	HonorHealth Research Institute	Scottsdale	Arizona	United States	852558
3	USC/Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
4	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
5	UC Davis Medical Center	Sacramento	California	United States	95817
6	Simlow Cancer Hospital at Yale	New Haven	Connecticut	United States	06510
7	Emory University winship Cancer Institute	Atlanta	Georgia	United States	30322
8	Robert H. Lurie Comprehensive Cancer Center of Northwestern University	Chicago	Illinois	United States	60611
9	The Sidney Kimmel Comprehensive Cancer Center at John Hopkins	Baltimore	Maryland	United States	21287
10	Tufts Medical Center	Boston	Massachusetts	United States	02111
11	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
12	University of Michigan	Ann Arbor	Michigan	United States	48109
13	Dartmouth-Hitchcock Medical Center (DHMC)	Lebanon	New Hampshire	United States	03766
14	Summit Medical Group - Florham Park Campus/Atlantic Health	Florham Park	New Jersey	United States	07932
15	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
16	New York University Langone Medical Center	New York	New York	United States	10016
17	New York Presbyterian Hospital Columbia University Medical Center	New York	New York	United States	10019
18	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
19	Rochester Skin Lymphoma Medical Group	Rochester	New York	United States	14450
20	Wake Forest Baptist Health	Winston-Salem	North Carolina	United States	27157
21	The Ohio State University and Wexner Medical Center, James Cancer Hospital	Columbus	Ohio	United States	43210
22	University of Oklahoma Stephenson Cancer Center	Oklahoma City	Oklahoma	United States	73104
23	Oregon Health and Science University	Portland	Oregon	United States	97239
24	West Penn Hospital	Pittsburgh	Pennsylvania	United States	15224
25	Hollings Cancer Center	Charleston	South Carolina	United States	29425
26	Vanderbilt Ingram Cancer Center	Nashville	Tennessee	United States	37212
27	MD Anderson Cancer Center	Houston	Texas	United States	77030
28	CliniCore Texas	Houston	Texas	United States	77079
29	START- South Texas Accelerated Research Therapeutics	San Antonio	Texas	United States	78229
30	Virgina Commonwealth University	Richmond	Virginia	United States	23298
31	University of Washington, Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
32	Centre Hospitalier Universitaire Universite Catholique de Louvain - Site Godinne	Yvoir	Namur	Belgium	B-5530
33	Universitair Ziekenhuis Gent	Gent	Oost-Vlaanderen	Belgium	9000
34	Intitut Jules Boredt	Bruxelles		Belgium	1000
35	Tom Baker Cancer Centre	Calgary	Alberta	Canada
36	British Columbia Cancer Agency	Vancouver	British Columbia	Canada	V5Z 4E6
37	Cancer Care Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
38	Nova Scotia Health Athority-Qeii HSC	Halifax	Nova Scotia	Canada	B3H 2Y9
39	Sunnybrook Hospital	Toronto	Ontario	Canada	M4N 3M5
40	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M56 2M9
41	Jewish General Hospital	Montréal	Quebec	Canada	H3T 1E2
42	Gustave Roussy Cancer Campus (IGR)	Villejuif	Cedex	France	94805
43	Centre Hospitalier Lyon Sud	Pierre-Bénite	Lyon	France	69310
44	Institut Bergonié, Unicancer	Bordeaux		France	33000
45	Centre Antoine Lacassagne, Oncologie Médicale	Nice		France	06189
46	Centre Henri Becquerel, Hematology	Rouen		France	1,76-38
47	Institut Universitaire du Cancer - Oncopôle, Department d'Hématologie	Toulouse Cedex 9		France	31059
48	CRU de Tours - Hôpital Bretonneau, Hématologie -Thérapy Cellulaire	Tours		France	37044
49	Semmelweis Egyetem - I. sz. Belgyógyászati Klinika	Budapest		Hungary	1083
50	Debreceni Egyetem Klinikai Központ	Debrecen		Hungary	4032
51	Szabolcs-Szatmár-Bereg Megyei Kórházak És Egyetemi Oktatókórház	Nyíregyháza		Hungary
52	Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi	Bologna		Italy	40138
53	Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia	Brescia		Italy	25123
54	Instituto Europeo di Oncologia	Milan		Italy
55	Azienda Socio Santaria Territoriale Monza- Osperdale San Gerado	Monza		Italy
56	Institut Catala d'Oncologia	Girona	Giona	Spain
57	imCORE - Clínica Universidad de Navarra	Pamplona	Navarra	Spain	31008
58	Hospital Universitario Fundacion Jimenez Diaz Preview	Madrid		Spain	28040
59	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
60	University Hospitals of Leicester NHS Trust	Leicester	East Midlands	United Kingdom	LE1 5WW
61	University Hospital Southhampton NHS Foundation Trust - Somers Cancer Research	Southampton	Hampshire	United Kingdom	SO16 6YD
62	Churchill Hospital, Oxford University Hospital NHS Trust	Oxford	Oxfordshire	United Kingdom	OX3 7LE
63	The Royal Marsden NHS Foundation Trust	Sutton	Surrey	United Kingdom	SM2 5PT
64	University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital	Birmingham		United Kingdom	B15 2TH
65	Beatson Cancer Center and University of Glasgow	Glasgow		United Kingdom	G12 0XL
66	University College London Hospitals NHS Foundation Trust	London		United Kingdom	NW1 2PG
67	Guy's and Saint Thomas' NHS Foundation Trust	London		United Kingdom	SE1 9RT
68	The Christie NHS Foundation Trust, Christie Hospital	Manchester		United Kingdom	M20 4BX
69	The Christie NHS Foundation Trust	Manchester		United Kingdom