975PD - A phase 1b study of AMG 386 plus paclitaxel and carboplatin in ovarian cancer patients undergoing primary or interval debulking surgery

Date 30 September 2012
Event ESMO Congress 2012
Session Gynecological cancers
Topics Drug Development
Ovarian Cancer
Presenter Ignace Vergote
Authors I.B. Vergote1, A. Oaknin Benzaquen2, J. Baurain3, S. Ananda4, S. Wong5, X. Yang6, B. Wu7, Z. Zhong8, M. Puhlmann9, A. Casado10
  • 1Obstetrics & Gynaecology, University Hospital Leuven, Leuven Cancer Institute, Leuven/BE
  • 2Medical Oncology, Vall d'Habron University Hospital, Barcelona/ES
  • 3Universite Catholique de Louvain, Bruxelles/BE
  • 4Oncology Unit, Royal Women's Hospital, Parkville/AU
  • 5Medical Oncology, Western Hospital, Footscray/AU
  • 6Department Of Biostatistics, Amgen Inc., Thousand Oaks/US
  • 7Department Of Pharmacokinetics And Drug Metabolism, Amgen Inc., Thousand Oaks/US
  • 8Department Of Clinical Immunology And Biological Sample Management, Amgen Inc., Thousand Oaks/US
  • 9Department Of Clinical Development, Amgen Inc., Thousand Oaks/US
  • 10Medical Oncology, Hospital Clínico San Carlos, 28040 - Madrid/ES

 

Abstract

Background

AMG 386, an investigational peptibody, blocks the interaction of angiopoietin-1 and -2 with the Tie2 receptor, thereby inhibiting tumor angiogenesis. We evaluated the tolerability of AMG 386 plus paclitaxel and carboplatin in ovarian cancer patients who had primary or interval debulking surgery (PDS or IDS, respectively).

Methods

Women (≥ 18 yrs, GOG ≤ 1) with high-risk stage I (grade 3 or aneuploid grade 1 or 2) or II-IV ovarian cancer received 6 cycles of the combination AMG 386 (15 mg/kg IV QW) plus paclitaxel (175 mg/m2 IV Q3W) and carboplatin (AUC 6 IV Q3W) followed by AMG 386 maintenance monotherapy up to 18 months. Patients had PDS; patients with disease stage IIIC or IV had the option of planned IDS. AMG 386 dosing was withheld for > 4 weeks after PDS or before IDS. The primary endpoint was the incidence of dose-limiting toxicities (DLTs), which determined cohort expansion to n = 25; secondary endpoints included the patient incidence of adverse events (AEs), the incidence of anti-AMG 386 antibody formation, and pharmacokinetics (PK). The current report presents results from the study's combination therapy phase.

Results

At interim analysis, 27 patients (14 PDS, 13 IDS) were enrolled and received ≥ 1 dose of AMG 386 plus paclitaxel and carboplatin. No patients experienced DLTs. The patient incidence of AEs is summarized in the table below. 4 of 24 patients developed non-neutralizing binding antibodies; 1 of 26 patients had pre-existing, non-neutralizing binding antibodies. Coadministration of AMG 386 did not alter the PK of paclitaxel or carboplatin.

AMG 386 +paclitaxel and carboplatin (n = 27)
Patient incidence of AEs – n (%) PDS (n = 14; 52%) IDS (n = 13; 48%)
Patients with any adverse event 14 (100) 12 (92)
Worst grade ≥ 3 7 (50) 5 (38)
Worst grade ≥ 4 3 (21)* 2 (15)**
Worst grade 5 0 (0) 0 (0)
In ≥ 20% of patients who had PDS or IDS Anygrade Worst grade ≥ 3 Anygrade Worst grade ≥ 3
Localized edema 8 (57) 0 (0) 3 (23) 0 (0)
Diarrhea 7 (50) 0 (0) 5 (38) 0 (0)
Nausea 7 (50) 0 (0) 6 (46) 0 (0)
Fatigue 7 (50) 0 (0) 5 (38) 0 (0)
Thrombocytopenia 3 (21) 1 (7) 6 (46) 2 (15)
Decreased appetite 2 (14) 0 (0) 6 (46) 0 (0)
Asthenia 6 (43) 0 (0) 4 (31) 0 (0)
Neutropenia 5 (36) 4 (29) 3 (23) 2 (15)
Nasopharyngitis 5 (36) 0 (0) 0 (0) 0 (0)
Alopecia 5 (36) 0 (0) 0 (0) 0 (0)
Abdominal distension 1 (7) 0 (0) 4 (31) 0 (0)
Abdominal pain 2 (14) 0 (0) 4 (31) 0 (0)
Constipation 4 (29) 0 (0) 4 (31) 0 (0)
Peripheral sensory neuropathy 4 (29) 0 (0) 4 (31) 0 (0)
Hypokalemia 0 (0) 0 (0) 4 (31) 1 (8)
Peripheral neuropathy 4 (29) 0 (0) 0 (0) 0 (0)
Parasthesia 4 (29) 0 (0) 1 (8) 0 (0)
Vomiting 2 (14) 0 (0) 3 (23) 0 (0)
Musculoskeletal pain 2 (14) 0 (0) 3 (23) 0 (0)
Anemia 3 (21) 0 (0) 3 (23) 1 (8)
Mucosal inflammation 3 (21) 0 (0) 1 (8) 0 (0)
Myalgia 3 (21) 0 (0) 1 (8) 0 (0)
Dizziness 3 (21) 0 (0) 2 (15) 0 (0)
Dysgeusia 3 (21) 0 (0) 1 (8) 0 (0)
Of specific interest
Edema
Generalized 2 (14) 0 (0) 0 (0) 0 (0)
Lymphedema 2 (14) 1 (7) 1 (8) 0 (0)
Female genital tract fistula 0 (0) 0 (0) 1 (8) 0 (0)
Wound 0 (0) 0 (0) 1 (8) 0 (0)

*Grade 4 AEs were neutropenia (n = 3).

** Grade 4 AEs were neutropenia (n = 1) and thrombocytopenia (n = 1).

Conclusions

Interim results from this Phase 1b study of ovarian cancer patients undergoing PDS or IDS suggest that AMG 386 at 15 mg/kg IV QW plus paclitaxel and carboplatin was tolerable. No PK interactions were observed between AMG 386 and paclitaxel or carboplatin.

Disclosure

I.B. Vergote: As is relevant for the current drug, I am an advisory board member for and received funding from Amgen. However, I am also an advisory board member and received funding from other companies. J. Baurain: Corporate-sponsored research: Academic clinical trial run with an Amgen product in squamous skin cancer. X. Yang: Stock ownership: Amgen I am an employee with Amgen. B. Wu: Stock ownership: Amgen I am an employee at Amgen. Z. Zhong: Stock ownership: Amgen I am an employee at Amgen. M. Puhlmann: Stock ownership: Amgen I am an employee at Amgen. All other authors have declared no conflicts of interest.