EMR 20006-012: A phase II randomized double-blind placebo controlled trial comparing the combination of pimasertib (MEK inhibitor) with SAR245409 (PI3K inhibitor) to pimasertib alone in patients with previously treated unresectable borderline or low grade ovarian cancer.

Abstract

OBJECTIVE:

To compare the combination of a MEK inhibitor (pimasertib) and a PI3K inhibitor (SAR245409) to pimasertib alone in recurrent unresectable borderline/low malignant potential (LMP) or low-grade serous ovarian carcinoma (LGSOC), determining whether combination is superior.

METHODS:

Patients with previously treated, recurrent LMP or LGSOC with measurable disease received either combination of pimasertib (60 mg daily) + SAR245409 (SAR) (70 mg daily) or pimasertib alone (60 mg BID) until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR) by RECIST 1.1, determining whether combination was superior to pimasertib alone. Secondary endpoints included progression free survival (PFS), disease control, and adverse events.

RESULTS:

Sixty-five patients were randomized between September 2012 and December 2014. ORR was 9.4% (80% CI, 3.5 to 19.7) in the combination arm and 12.1% (80% CI, 5.4 to 22.8) in the pimasertib alone arm. Median PFS was 7.23 months (80% CI, 5.06 to -) and 9.99 (80% CI, 7.39 to 10.35) for pimasertib alone and pimasertib + SAR, respectively. Six-month PFS was 63.5% (80% CI, 47.2% to 75.9%) and 70.8% (80% CI, 56.9% to 80.9%). Eighteen (56.3%) patients in the combination arm and 19 (57.6%) patients in the pimasertib alone arm discontinued the trial. The study was terminated early because of low ORR and high rate of discontinuation.

CONCLUSIONS:

Response to pimasertib alone (ORR 12%) suggests that MEK inhibition could be used as an alternative treatment method to cytotoxic chemotherapy in this population. The MEK inhibitor alone was as effective as the combination, although the trial was limited by small numbers. Additional studies investigating the role of single agent or combination MEK and PI3K inhibition are warranted to further evaluate the utility of these treatments and describe a standard of care for LGSOC.

• Authors: Rebecca C Arend, Allison M Davis, Przemyslaw Chimiczewski, David M O'Malley, Diane Provencher, Ignace Vergote, Sharad Ghamande, Michael J Birrer
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 156 Issue 2 Pg. 301-307 (02 2020) ISSN: 1095-6859 [Electronic] United States
• PMID: 31870556 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial)
• Copyright: Copyright © 2019. Published by Elsevier Inc.

Chemical References

• N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Quinoxalines
• Sulfonamides
• XL765
• Niacinamide
• MAP2K2 protein, human
• MTOR protein, human
• TOR Serine-Threonine Kinases
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Double-Blind Method
• Female
• Humans
• MAP Kinase Kinase 1 (antagonists & inhibitors, metabolism)
• MAP Kinase Kinase 2 (antagonists & inhibitors, metabolism)
• Middle Aged
• Neoplasm Grading
• Neoplasm Recurrence, Local (drug therapy, enzymology, pathology)
• Neoplasm Staging
• Niacinamide (administration & dosage, analogs & derivatives, therapeutic use)
• Ovarian Neoplasms (drug therapy, enzymology, pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors (administration & dosage)
• Protein Kinase Inhibitors (administration & dosage)
• Quinoxalines (administration & dosage)
• Sulfonamides (administration & dosage)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Young Adult