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A Phase IB Trial of the PI3K Inhibitor Alpelisib and Weekly Cisplatin in Patients with Solid Tumor Malignancies.
Tsang, Erica S; Aggarwal, Rahul R; Dhawan, Mallika S; Bergsland, Emily K; Alvarez, Edwin A; Calabrese, Susan; Pacaud, Romain; Garcia, Jose; Fattah, Delaire; Thomas, Scott; Grabowsky, Jennifer; Moasser, Mark M; Munster, Pamela N.
Afiliação
  • Tsang ES; Division of Hematology and Oncology, University of California San Francisco, San Francisco, California.
  • Aggarwal RR; Division of Hematology and Oncology, University of California San Francisco, San Francisco, California.
  • Dhawan MS; Division of Hematology and Oncology, University of California San Francisco, San Francisco, California.
  • Bergsland EK; Division of Hematology and Oncology, University of California San Francisco, San Francisco, California.
  • Alvarez EA; Division of Hematology and Oncology, University of California San Francisco, San Francisco, California.
  • Calabrese S; Division of Hematology and Oncology, University of California San Francisco, San Francisco, California.
  • Pacaud R; Division of Hematology and Oncology, University of California San Francisco, San Francisco, California.
  • Garcia J; Division of Hematology and Oncology, University of California San Francisco, San Francisco, California.
  • Fattah D; Division of Hematology and Oncology, University of California San Francisco, San Francisco, California.
  • Thomas S; Division of Hematology and Oncology, University of California San Francisco, San Francisco, California.
  • Grabowsky J; Division of Hematology and Oncology, University of California San Francisco, San Francisco, California.
  • Moasser MM; Division of Hematology and Oncology, University of California San Francisco, San Francisco, California.
  • Munster PN; Division of Hematology and Oncology, University of California San Francisco, San Francisco, California.
Cancer Res Commun ; 2(7): 570-576, 2022 07.
Article em En | MEDLINE | ID: mdl-36923283
ABSTRACT
The PI3K pathway may be a potential mechanism to overcome cisplatin resistance. We conducted a phase Ib trial of alpelisib and cisplatin for patients with solid tumor malignancies with planned dose expansion in HPV-associated tumors. The primary objective was to determine the MTD and recommended phase II dose. Two different weekly doses of cisplatin (30 and 35 mg/m2) were evaluated with escalating doses of alpelisib, administered daily during a 21-day treatment cycle. Twenty-three patients were enrolled 91% received >3 prior regimens with median of 4 (range 1-10), and 78% progressed on prior platinum. The MTD was alpelisib 250 mg daily with weekly cisplatin 30 mg/m2. There were 3 DLTs all grade 4 hyperglycemia. Frequent treatment-related adverse events of any grade included fatigue (52%), diarrhea (39%), nausea (38%), hyperglycemia (30%), anemia (22%), and nephropathy (17%). Hyperglycemia was linked to baseline hemoglobin A1C, but not body mass index. Twelve patients discontinued treatment for toxicity (n = 9 during cycle 1) and 11 discontinued for progression. Of 14 evaluable patients who received at least one treatment cycle, 4 (29%) patients demonstrated partial response, and 7 had stable disease for a disease control rate of 79%. The median PFS measured 4.3 months (95% CI, 1.6-4.5). No difference in PFS was observed between PIK3CA-mutated and wild-type tumors. While the combination of alpelisib and cisplatin demonstrated preliminary evidence of activity despite platinum resistance, toxicities hindered prolonged treatment. Prospective studies are planned using carboplatin and alpelisib to improve toxicity and tolerability.

Significance:

The PI3K inhibitor alpelisib has limited activity alone, but there is interest in combinations in platinum-resistant tumors. In this phase Ib study of alpelisib with cisplatin, the objective response rate measured 29% but adverse events limited dose intensity. These promising results provide rationale for studying combinations with better tolerated platinum agents.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cisplatino / Neoplasias Tipo de estudo: Observational_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Cancer Res Commun Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cisplatino / Neoplasias Tipo de estudo: Observational_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Cancer Res Commun Ano de publicação: 2022 Tipo de documento: Article