PrimaryAssess the safety profile of pasireotide s.c. during the first 8 weeks of treatment with pasireotide s.c.SecondaryAssess the safety profile of pasireotide s.c.at study completionAssess tumor response as measured by disease control rate (DCR)…
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
No registrations found.
Outcome measures
Primary outcome
Incidence of AEs, laboratory, vital signs and electrocardiographic
abnormalities. Changes in laboratory values, electrocardiograms readings, and
in vital signs values.
Secondary outcome
DCR (CR, PR,SD) per RECIST 1.0
For each cycle, PK parameters on Day 1 and on day 8 at steady state
Changes from baseline on melanoma response biomarkers (S100B) overtime and its
correlation with each dose
Background summary
This trial focusses onto 2 disease areas, Metastatic Melanoma without NRAS or
BRAF mutation and Merkel Cell Carcinoma
Merkel cell carcinoma (MCC) is a rare tumor, accounting for less than 1% of
cutaneous malignancies. A recent study showed that the incidence increased
over a 15-year period (from 0.15 case per 100,000 in 1986 to 0.44 case per
100,000 in 2001). Overall, the 2-year mortality rate is 30-50%; To date, there
is no standard protocol for the management of MCC and surgical treatment of
large tumors especially in the head and neck region can be disfiguring . There
is an urgent need for new therapies to treat patients with MCC.
The pasireotide s.c. formulation has been evaluated in healthy volunteers, and
in patients with acromegaly, metastatic carcinoid tumors, and Cushing*s disease
It has been shown that SSTRs are expressed in tumor tissue from patients with
melanoma. Overall expression was considered high
Preclinical studies with SSAs have shown inhibition of melanoma growth both in
vitro and in vivo.
The MAPK pathway is controlling cellular growth, differentiation and cell
survival. Deregulation of MAPK pathway is common in many human cancers
including melanoma. Somatostatin has been shown to inhibit MAPK activity.
However melanoma also has a high frequency of activating mutations in BRAF and
NRAS that have been shown to result in constant activation of MAPK pathway and
eventually contribute to proliferation and differentiation in many types of
cancer. Since SSAs act through SSTR upstream of MAPK pathway, inhibition of
MAPK activity by SSA may influence tumor growth to a lesser degree, or not at
all, when the MAPK pathway is constitutively activated by BRAF and/or NRAS
mutations. Therefore, patients harboring such activating mutations will not be
included in this trial.
Study objective
Primary
Assess the safety profile of pasireotide s.c. during the first 8 weeks of
treatment with pasireotide s.c.
Secondary
Assess the safety profile of pasireotide s.c.at study completion
Assess tumor response as measured by disease control rate (DCR)
Assess the PK of pasireotide s.c.
Assess the effect of pasireotide s.c., at each dose level, on melanoma response
biomarkers (S100b) over time
Assess the effect of pasireotide s.c. on potential response and/or secretion
biomarkers over time
Study design
open label, single arm, multi-center, intra-patient dose escalation, phase I
study
there are three phases:
screening (28days)
intra-patient dose-escalation (4*2 weeks)
follow-up phase (6 months)
Intervention
pasireotide s.c.
intrapatient escalating over de course of 8 weeks: 2 weeks 300 ug TID, 2 weeks
600ug TID, 2 weeks 900ug TID, 2 weeks 1200ug, plus 2 additional weeks during
the LAR start up due to bloodlevels
pasireotide LAR im.
The 8 week period is followed by 6 months 80 mg every 28 days or lower, in case
of toxicity.
Study burden and risks
Toxicities due to the trial drugs pasireotide. Please refer to the Patient
information Sheet for een detailled overview
Other risks:
Taking blood and tumorbiopsies may cause pain, bleeding, and/or bruising.
Patients will be exposed to radiation (CT-scan, MUGA-scan and/or X-rays,
FDG-PET). The radiation exposure will not exceed the maximum ranges that are
set within the Netherlands.
Allergic reaction on contrast fluids used.
Raapopseweg 1
Arnhem 6824DP
NL
Raapopseweg 1
Arnhem 6824DP
NL
Listed location countries
Age
Inclusion criteria
1. Adult male or female, age *18 years
2. Female patients of child bearing potential must have a negative pregnancy test at screening
3. Histologically or cytologically confirmed unresectable (stage III) and/or metastatic (stage IV) melanoma or unresectable and/or metastatic Merkel cell carcinoma
4. No mutation in BRAF and NRAS genes (for melanoma patients only)
5. Patients must have lesions that can be biopsied
6. Presence of measurable or non-measurable disease according to RECIST 1.0 (Appendix 14.1)
7. ECOG Performance Status of 0 or 1
8. Adequate organ function
* WBC * 2.5 x 109/L
* ANC * 1.5 x 109/L
* Platelets * 100 x 109/L
* Hemoglobin * 9 g/dL
* Serum creatinine * 1.5 mg/dL
* Serum lipase * 1.5 ULN
9. Life expectancy of at least 12 weeks
Exclusion criteria
1. Patients with unknown BRAF or NRAS mutational status (for melanoma patients only)
2. Primary uveal melanoma
3. Patients with symptomatic CNS metastases who are neurologically unstable or requiring increasing doses of steroids to control their CNS disease
4. Prior treatment with somatostatin analogue or radiolabeled somatostatin analogs
5. Patients for whom standard treatment is available and indicated due to rapidly progressive or aggressive disease
6. Patients who received more than 3 prior lines of systemic therapy for the treatment of the disease
7. Patients receiving any anti-neoplastic therapy within the 4 weeks prior to baseline
8. Patients with known gallbladder or bile duct disease, acute or chronic pancreatitis
9. Patients with abnormal coagulation (PT or PTT elevated by 30% above normal limits)
10. Patients on continuous anticoagulation therapy.
11. Patients who are not biochemically euthyroid
12. QT-related exclusion criteria
* Baseline QTcF >450 ms
* History of syncope or family history of idiopathic sudden death
* Known history of prolong QT syndrome
* Sustained or clinically significant cardiac arrhythmias
13. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study
14. Pregnant or nursing (lactating) women
15. Women of child-bearing potential, UNLESS they are
* Women whose sexual orientation precludes intercourse with a male partner
* Women whose partners have been sterilized by vasectomy or other means
* Using a highly effective method of birth control
16. Baseline ALT or AST > 3 x ULN
17. Baseline total bilirubin > 1.5x ULN
18. Presence of Hepatitis B surface antigen (HbsAg)
19. Presence of Hepatitis C antibody test (anti-HCV)
20. History of, or current alcohol misuse/abuse within the past 12 months prior to visit 1 (baseline)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
EudraCT | EUCTR2013-004573-27-NL |
ClinicalTrials.gov | NCT01652547 |
CCMO | NL47322.041.14 |