Clinical Trial: A Phase I, Exploratory, Intra-patient Dose Escalation Study to Investigate the Preliminary Safety, Pharmacokinetics, and Anti-tumor Activity of Pasireotide (SOM230) s.c.Followed by Pasireotide LAR in Patients With Metastaticmelanoma or Metastatic Merkel Cell Carcinoma

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: A Phase I, Exploratory, Intra-patient Dose Escalation Study to Investigate the Preliminary Safety, Pharmacokinetics, and Anti-tumor Activity of Pasireotide (SOM230) s.c.Followed by Pasireotide LAR in

Brief Summary:

This study will evaluate the preliminary safety, pharmacokinetics, and anti-tumor activity of pasireotide s.c. in patients with metastatic melanoma or metastatic Merkel cell carcinoma. The study consists of three phases: screening, intra-patient dose-escalation, and follow-up phases.

In the screening phase patient will be informed of all aspects of the study and sign informed consent forms and then be screened for study eligibility.

During the intra-patient dose escalation phase, 18 patients will be treated with pasireotide s.c. 300 μg t.i.d. for 2 weeks. If there are no unacceptable AEs, defined as drug-related clinically meaningful, uncontrolled grade 3 or any grade 4 toxicities, patients will be dose escalated to 600 μg t.i.d. for 2 more weeks, then 900 μg t.i.d. for 2 weeks and then 1200 μg for 2 weeks provided that there are no unacceptable AEs. Each patient will be in the dose escalation phase for a maximum of 8 weeks.

At end of the intra-patient dose escalation phase, patients will be allowed to switch to 80 mg pasireotide LAR i.m. q 28 d (or a lower dose in case of toxicity) for an additional 6 months or until disease progression, or unacceptable AEs, or patient withdraws consent. In addition, all patients will keep their pasireotide s.c. t.i.d. treatment (same dose as that at the end of the 8-week dose escalation phase) during the first 2 weeks of the LAR follow-up phase, except on the day receiving the first LAR dose because of an anticipated initial burst of drug release.

Detailed Summary:
Sponsor: Novartis Pharmaceuticals

Current Primary Outcome:

• Number of patients with AEs, SAEs [ Time Frame: Week 8 ]
  Number of patients with AEs (overall and by severity) SAEs according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
• Number of patients with laboratory abnormalities and changes in laboratory values [ Time Frame: Week 8 ]
  Number of patients with laboratory abnormalities according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
• Number of patients with electrocardiographic abnormalities and changes in electrocardiograms readings [ Time Frame: Week 8 ]
  Number of patients with ECG according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
• Number of patients with vital sign abnormalities and changes in vital signs [ Time Frame: Week 8 ]
  Number of patients with vital sign abnormalities according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0

Original Primary Outcome:

• Number of patients with AEs, SAEs, laboratory, vital signs and electrocardiographic abnormalities and changes in laboratory values, electrocardiograms readings, and vital signs [ Time Frame: Week 8 ]
  Number of patients with AEs (overall and by severity) SAEs, ECG, laboratory and vital signs abnormalities according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
• Number of patients with AEs, SAEs, laboratory, vital signs and electrocardiographic abnormalities and changes in laboratory values, electrocardiograms readings, and vital signs values at study completion [ Time Frame: Day 253 ]
  Number of patients with AEs (overall and by severity) SAEs, ECG, laboratory and vital signs abnormalities according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

Current Secondary Outcome:

• Changes in laboratory values, electrocardiograms readings, and vital signs values at study completion [ Time Frame: Baseline, Day 253 ]
• Tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST 1.0) as measured by disease control rate ((DCR), (Complete Response (CR), Partial Response (PR), Stable Disease (SD)) [ Time Frame: Baseline, Day 57, Day 113, Day 169, Day 225 ]
  Tumor response as measured by DCR defined as the proportion of patients with best overall response of complete response (CR), partial response (PR) or stable response (SR) according to the RECIST Version 1.0 Criteria.
• PK parameters for each cycle on Day 1 (Cmax,d1 Tmax,d1, AUC0-2hr,d1), and on day 8 at steady state (Cmin,d8, Cmaxd8, Tmax,d8, Cavg,d8, AUC0-2hr,d8, ARd8) [ Time Frame: Day 1, 8, 15, 22, 29, 36, 43, 50, 57, 85, 113, 141, 169, 197 and 225 ]
  Pasireotide plasma concentrations will be summarized by dose and time and PK profile of pasireotide concentration over time will be generated by dose.
• Changes from baseline on melanoma response biomarkers (MIA, S100B) overtime and its correlation with each dose [ Time Frame: Baseline, Day 8, 15, 22, 29, 36, 43, 50, 57, 113, 169 and 225 ]
  Melanoma response biomarkers (MIA, S100B) will be evaluated in pre- and post-treatment samples on all patients to assess the biochemical response to pasireotide as change from baseline at Day 8, 15, 22, 29, 36, 43, 50, 57, 113, 169 and 225.
• Changes from baseline and/or actual levels of potential response and/or secretion biomarkers over time, in repeated tumor and/or blood samples [ Time Frame: Baseline, Day 1, 15, 29, 43, 57, 113, 169 and 225 ]
  PD and cellular effect makers in tumor Protein expression levels for different PD markers such as p4EBP-1, pS6, pAKT, pERK and for different cellular effect markers of proliferation and apoptosis (such as Ki67, cyclin D1, cleaved caspase, PARP), angiogenesis (such as microvessel density) and secretion (such as IGF-1 receptor); change from baseline of these markers at day 29 and 57.
• Number of patients with AEs, SAEs at study completion [ Time Frame: Day 253 ]
  Number of patients with AEs (overall and by severity) SAEs according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0
• Number of patients with electrocardiographic abnormalities and changes in electrocardiograms readings at study completion [ Time Frame: Day 253 ]
  Number of patients with ECG abnormalities according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
• Number of patients with laboratory abnormalities and changes in laboratory values at study completion [ Time Frame: Day 253 ]
  Number of patients with laboratory abnormalities according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0
• Number of patients with vital sign abnormalities and changes in vital signs at study completion [ Time Frame: Day 253 ]
  Number of patients with vital sign abnormalities and changes in vital signs according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0

Original Secondary Outcome:

• Changes in laboratory values, electrocardiograms readings, and vital signs values at study completion [ Time Frame: Baseline, Day 253 ]
• Tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST 1.0) as measured by disease control rate ((DCR), (Complete Response (CR), Partial Response (PR), Stable Disease (SD)) [ Time Frame: Baseline, Day 57, Day 113, Day 169, Day 225 ]
  Tumor response as measured by DCR defined as the proportion of patients with best overall response of complete response (CR), partial response (PR) or stable response (SR) according to the RECIST Version 1.0 Criteria.
• PK parameters for each cycle on Day 1 (Cmax,d1 Tmax,d1, AUC0-2hr,d1), and on day 8 at steady state (Cmin,d8, Cmaxd8, Tmax,d8, Cavg,d8, AUC0-2hr,d8, ARd8) [ Time Frame: Day 1, 8, 15, 22, 29, 36, 43, 50, 57, 85, 113, 141, 169, 197 and 225 ]
  Pasireotide plasma concentrations will be summarized by dose and time and PK profile of pasireotide concentration over time will be generated by dose.
• Changes from baseline on melanoma response biomarkers (MIA, S100B) overtime and its correlation with each dose [ Time Frame: Baseline, Day 8, 15, 22, 29, 36, 43, 50, 57, 113, 169 and 225 ]
  Melanoma response biomarkers (MIA, S100B) will be evaluated in pre- and post-treatment samples on all patients to assess the biochemical response to pasireotide as change from baseline at Day 8, 15, 22, 29, 36, 43, 50, 57, 113, 169 and 225.
• Changes from baseline and/or actual levels of potential response and/or secretion biomarkers over time, in repeated tumor and/or blood samples [ Time Frame: Baseline, Day 1, 15, 29, 43, 57, 113, 169 and 225 ]
  PD and cellular effect makers in tumor Protein expression levels for different PD markers such as p4EBP-1, pS6, pAKT, pERK and for different cellular effect markers of proliferation and apoptosis (such as Ki67, cyclin D1, cleaved caspase, PARP), angiogenesis (such as microvessel density) and secretion (such as IGF-1 receptor); change from baseline of these markers at day 29 and 57.

Information By: Novartis

Dates:
Date Received: July 12, 2012
Date Started: November 2012
Date Completion:
Last Updated: March 20, 2016
Last Verified: March 2016