SGI-110 in Combination With Carboplatin in Ovarian Cancer (SGI-110)

A Randomized, Controlled, Open-Label, Phase 2 Trial of SGI-110 and Carboplatin in Subjects With Platinum-Resistant Recurrent Ovarian Cancer

A 2-part, Phase 2 controlled, open-label, randomized study in participants with platinum-resistant recurrent ovarian cancer. In Part 1, participants received SGI-110 and carboplatin. The optimum dose of SGI-110 (guadecitabine) was identified in Part 1 based on safety and efficacy. In Part 2, participants were randomized to receive the dose identified in Part 1 plus carboplatin or one of four treatment of choice at the discretion of the investigator. The treatment of choice consisted of topotecan, pegylated liposomal doxorubicin, paclitaxel or gemcitabine.

Study Overview

• Status: Completed
• Conditions: Ovarian Cancer
• Intervention / Treatment: Drug: Carboplatin; Drug: SGI-110; Drug: Treatment of Choice (topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine)

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Juravinski Cancer Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital
  • Quebec
    • Montreal, Quebec, Canada, H2L 4M1
      • CHUM Gynecologie-Oncologie, Notre Dame Hospital
• United Kingdom
  • Bristol, United Kingdom, BS2 8ED
    • Bristol Heamatology and Oncology Centre
  • Leeds, United Kingdom, LS9 7TF
    • St. James Univesity Hospital - St. James Institute of Oncology
  • London, United Kingdom, EC1V 4AD
    • Cambridge University Hospitals NHS Foundation and Trust
  • London, United Kingdom, NW1 2PG
    • Univesity College Hospital
  • London, United Kingdom, W12 0NN
    • Imperial College Health Care NHS Trust-Garry Weston Centre
  • Middlesex, United Kingdom, HA6 2RN
    • Mount Vernon Cancer Centre
  • Sutton, United Kingdom, SM2 5PT
    • Royal Marsden Foundation Trust
• United States
  • California
    • Los Angeles, California, United States, 90033
      • Norris Comprehensive Cancer Center- University of Southern California
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida Shands Cancer Center
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Georgia Health Sciences University
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Melvin and Bren Simon Cancer Center- Indiana University
  • Louisiana
    • Covington, Louisiana, United States, 70433
      • Women's Cancer Care
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins Kimmel Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute
  • New York
    • Brightwaters, New York, United States, 11718
      • Island Gynecologic Oncology
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Cancer Institute- Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Cancer Institute
  • Texas
    • Dallas, Texas, United States, 75201
      • Mary Crowley Medical Research Center
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Fairfax Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Participants who are women 18 years of age or older.
2. Participants who have histologically or cytologically confirmed recurrent high-grade serous epithelial ovarian cancer (Grade 2 or 3), primary peritoneal carcinomatosis or fallopian tube cancer.
3. Participants who have platinum-resistant disease (defined as having relapsed within 6 months of her last platinum-containing regimen). There is no limit on the number of prior treatment regimens in Part 1. In Part 2, participants may have had no more than 3 prior cytotoxic treatment regimens, excluding adjuvant or maintenance therapy.
4. Participants must have had prior paclitaxel treatment.
5. Participants who have measurable disease according to RECIST v1.1 or detectable disease.
6. Participants with ECOG performance status of 0 or 1.
7. Participants with acceptable organ function.
8. Participants must be at least 3 weeks from last chemotherapy.

Exclusion Criteria:

1. Participants who have hypersensitivity to SGI-110 and/or carboplatin or other components of these drug products.
2. Participants who have received prior therapy with any hypomethylating agents.
3. Participants who are refractory to platinum treatment i.e., progressed while on platinum treatment.
4. Participants with abnormal left ventricular ejection fraction.
5. Participants with Grade 2 or greater neuropathy.
6. Participants with known brain metastases.
7. Participants with known history of HIV, HCV or HBV.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SGI-110 + Carboplatin; Stage 1 was a safety lead-in stage with a dose escalation design. Participants were evaluated with the combination of SGI-110 (guadecitabine) plus carboplatin (G+C), given as 28-day treatment cycles: guadecitabine administered subcutaneous (SC) daily on Days 1-5, at a starting dose of 45 mg/m2/day in Cohort 1, followed by carboplatin intravenous (IV) based on a targeted dose of area under the curve (AUC) 5 on Day 8. After dose limiting toxicities were noted, guadecitabine dose was reduced to 30 mg/m2/day for subsequent cycles for 4 participants. Cohort 2 received 30 mg/m2/day guadecitabine and carboplatin IV AUC 4.	Drug: Carboplatin; Drug: SGI-110; Other Names: guadecitabine
Experimental: SGI-110 + Carboplatin or TC; Stage 2 was an open-label, randomized, controlled trial. Eligible participants were randomly assigned in a 1:1 ratio to receive either (1) G+C combination treatment in 28-day cycles at 30 mg/m2 SC once daily on Days 1-5 and carboplatin IV AUC 4 on Day 8, or (2) treatment of choice (TC) of topotecan, pegylated liposomal doxorubicin (PLD), paclitaxel, or gemcitabine based on recommended dosing in 28-day cycles; participants initially randomized to TC were able to cross over to receive 30 mg/m2 G+C due to disease progression.	Drug: Carboplatin; Drug: SGI-110; Other Names: guadecitabine; Drug: Treatment of Choice (topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine); Investigator chose to treat with either topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stage 1: Dose Limiting Toxicities	Number of participants with dose limiting toxicities (DLTs) in Stage 1	Up to 12 months
Stage 2: Progression Free Survival	Progression free survival (PFS) time was defined as the time interval from the date of the first dose of study medication until the earlier of disease progression or death. Participants were treated with their assigned treatment [guadecitabine+carboplatin (G+C) or treatment choice (TC)] until disease progression or unacceptable treatment-related toxicity occurred.	Up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate	The objective response rate (ORR) was defined as the proportion of participants who experienced an objective response (best overall response of complete response/full response or partial response, which was confirmed by a subsequent assessment at least 28 days later). Response categories were determined based on RECIST v1.1 criteria, or on modified Rustin (CA-125) criteria if response assessment could not be made using RECIST criteria.	Up to 24 months
Progression Free Survival at 6 Months	Progression free survival rate at 6 months is the proportion of participants who were alive and did not have disease progression at 6 months after start of treatment.	6 months
Clinical Benefit Rate	Clinical benefit rate (CBR) was defined as the proportion of subjects who experienced a best overall response of complete response/full response or partial response (confirmed by a subsequent assessment at least 28 days later), or documented stable disease for at least 3 months after the first dose. Response categories were determined based on RECIST v1.1 criteria, then based on modified Rustin (CA-125) criteria if assessment could not be made using RECIST criteria.	Up to 24 months
CA-125 Levels	Percentage of participants with CA-125 reduction by ≥ 50% from baseline	Up to 24 months
Duration of Response	Duration of response is defined as the time between the date of the first documentation of complete response/full response or partial response, and the date of disease progression or date of death due to any cause, or the last adequate tumor assessment prior to the start of subsequent anti-cancer therapy including crossing over to G+C from TC arm, whichever occurred earlier. Only participants who responded were included in the duration of response calculation.	Up to 24 months
Overall Survival	Overall survival was defined as the number of days from the day the participant was administered the first dose of study treatment to the date of death (regardless of cause). Survival time was censored on the last date the participant was known to be alive or lost to follow-up before reaching the event of death; in the TC group, time was censored at the date of crossover.	Up to 24 months
Stage 1: Pharmacokinetic Parameter Cmax	Time to maximum plasma concentration for guadecitabine, decitabine and carboplatin	Pre-dose and up to 8 hours post-dose on Cycle 1 Day 1 for guadecitabine and decitabine and Day 8 for carboplatin (28 day cycles)
Stage 1: Pharmacokinetic Parameter Tmax	Time to last measurable concentration for guadecitabine, decitabine and carboplatin	Pre-dose and up to 8 hours post-dose on Cycle 1 Day 1 for guadecitabine and decitabine and Day 8 for carboplatin (28 day cycles)
Stage 1: Pharmacokinetic Parameter AUC0-8	Area under the concentration-time curve from 0 to 8 hours (AUC0-8) for guadecitabine, decitabine and carboplatin	Pre-dose and up to 8 hours post-dose on Cycle 1 Day 1 for guadecitabine and decitabine and Day 8 for carboplatin (28 day cycles)

Collaborators and Investigators

• Sponsor: Astex Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Cardenas H, Fang F, Jiang G, Perkins SM, Zhang C, Emerson RE, Hutchins G, Keer HN, Liu Y, Matei D, Nephew K. Methylomic Signatures of High Grade Serous Ovarian Cancer. Epigenetics. 2021 Nov;16(11):1201-1216. doi: 10.1080/15592294.2020.1853402. Epub 2020 Dec 8.
• Oza AM, Matulonis UA, Alvarez Secord A, Nemunaitis J, Roman LD, Blagden SP, Banerjee S, McGuire WP, Ghamande S, Birrer MJ, Fleming GF, Markham MJ, Hirte HW, Provencher DM, Basu B, Kristeleit R, Armstrong DK, Schwartz B, Braly P, Hall GD, Nephew KP, Jueliger S, Oganesian A, Naim S, Hao Y, Keer H, Azab M, Matei D. A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer. Clin Cancer Res. 2020 Mar 1;26(5):1009-1016. doi: 10.1158/1078-0432.CCR-19-1638. Epub 2019 Dec 12.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): August 1, 2016

Study Registration Dates

• First Submitted: September 26, 2012
• First Submitted That Met QC Criteria: September 27, 2012
• First Posted (Estimate): September 28, 2012

Study Record Updates

• Last Update Posted (Actual): May 25, 2021
• Last Update Submitted That Met QC Criteria: April 30, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Ovarian Cancer
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Topoisomerase I Inhibitors; Gemcitabine; Carboplatin; Paclitaxel; Doxorubicin; Liposomal doxorubicin; Topotecan; Guadecitabine
• Other Study ID Numbers: SGI-110-02