Primary objective:* To assess the clinical efficacy of nilotinib, based on overall response rate (ORR), in thetreatment of c-Kit mutated melanoma in patients who have not received prior therapy withTKIs.Key secondary objectives:To assess the durable…
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Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The ORR, calculated as the proportion of patients with a best overall response
of confirmed
complete response or partial response (CR+PR).
Secondary outcome
Key secondary endpoints:
* ORR, calculated as the proportion of patients with a best overall response of
confirmed complete response or partial response (CR+PR).
* DORR, calculated as the rate of patients with a CR or PR lasting * 12 weeks.
* OS
Other secondary endpoints:
* PFS6
* OS12
* TOR, calculated as the time from date of randomization until first documented
response of CR or PR
* DOR, calculated as the time from the date of first documented CR or PR to the
first documented progression or death due to underlying cancer
* DCR, calculated as the proportion of patients with an overall response of CR,
PR or stable disease (SD) for a minimum of 12 weeks from randomization.
Exploratory endpoints
* Patient reported outcomes: health status and utility measured by EQ-5D;
functioning and QoL measured by FACT-G.
Safety endpoints:
Safety and tolerability.
Background summary
Melanoma is the most common tumor of the skin that develops from a neoplastic
transformation of melanocytes. The incidence of cutaneous melanoma is
increasing at a faster rate than for any other solid tumor (Rigel 1996, Marks
2000, SEER 2009) and is estimated as 68,000 new cases annually in the USA.
Globally, the incidence of melanoma varies by region, and according to World
Health Organization over 130,000 new cases of melanoma are recognized annually
around the world (WHO 2009). Melanoma is a tumor with significant impact on
society and when found to be metastatic, there is no effective treatments for
most patients. Although most patients have localized disease at the time of
diagnosis and are cured by surgical excision of the primary tumor metastases
can develop and most of these patients die of melanoma-associated causes. In
the USA, over 8,000 yearly deaths in 2008 have been associated with melanoma
(American Cancer Society).
Most melanomas develop in the skin (cutaneous melanoma).
Acral melanoma, which originates in the palms, soles and subungual regions,
represents about 5% of all melanomas, while mucosal melanomas, arising most
often on mucosal surfaces in the anorectal, vaginal and nasal sinus regions,
accounts for 1-2% (McLaughlin, et al 2005).
As acral and mucosal melanomas are often thicker at the time of diagnosis than
superficial melanoma, they have a higher propensity to recur and metastasize.
The overall median survival from diagnosis of stage IV melanoma has been
estimated to be 8 months (Lee, Tomsu, and Von Eschen 2000). One year survival
for these patients has been reported as approximately 25%, with approximately
15% of patients surviving 5 years (SEER 2009). In metastatic melanoma,
chemotherapy is used mostly with palliative intent. Currently registered agents
for the treatment of melanoma include the alkylating agent dacarbazine (DTIC)
and high dose IL-2. The administration of DTIC is a standard treatment with
response rates in the range of 5-15% and progression free survival of
approximately 8 weeks (Chapman, et al 1999). Cytotoxic therapies have not been
reported to prolong overall survival.
Recent investigations have provided some insight into the molecular events
which may lead to melanoma development and progression offering clues into
possible therapy options. Preliminary findings suggest that distinct subtypes
of melanoma are associated predominantly with the activation of BRAF, NRAS or
GNAQ, while others could be driven by the c-Kit pathway. The efforts to refine
the classification of melanoma have also proposed two subcategories of
superficial skin melanoma, chronic sun damaged (CSD) and non-CSD melanoma, as
well as better characterized melanomas of the acral and mucosal categories
(Curtin, et al 2006). Others have noted that melanomas associated with BRAF and
NRAS mutations have anatomic and age distribution differences compared with
patients harboring a mutation of c-Kit. Patients with cutaneous melanomas
associated with c-Kit mutations tend to be older and have lesions on the skin
in areas of chronic sun exposure. Mutations of c-Kit are also more prominent in
patients with acral and mucosal melanomas (Viros, et al 2008). Recently, three
Phase II trials employing imatinib in patients with metastatic/inoperable
melanoma harboring c-Kit mutations have reported early results. Response rates
have ranged from 28-50% with durable responses reported lasting 4-6+ months.
Study objective
Primary objective:
* To assess the clinical efficacy of nilotinib, based on overall response rate
(ORR), in the
treatment of c-Kit mutated melanoma in patients who have not received prior
therapy with
TKIs.
Key secondary objectives:
To assess the durable overall response rate (DORR) of patients treated with
nilotinib.
* To assess progression free survival (PFS) of patients treated with nilotinib.
* To assess overall survival (OS) of patients treated with nilotinib.
Other secondary objectives:
* To assess the time to objective response (TOR) and duration of overall
response (DOR)
from nilotinib treatment.
* To assess the disease control rate (DCR) from nilotinib treatment.
* To assess the PFS rate at 6 months (PFS6) and OS rate at 12 months (OS12) for
nilotinib
treatment.
Safety objectives:
* To assess the safety and tolerability profiles of nilotinib n this patient
population.
exploratory objectives
To assess changes in patient reported outcomes (PROs) including health status,
functioning, and quality of life (QoL).
Study design
This is a open-label, multi-center, single-arm, phase II study to assess the
efficacy of nilotinib (400 mg bid) every 3 weeks) in patients with c-Kit
mutated metastatic and/or inoperable melanoma. The primary efficacy endpoint is
ORR
Patients potentially eligible for the study will be consented for a
pre-screening visit. All patients must have their c-Kit status confirmed at a
central laboratory on paraffin embedded tissue.
Once c-Kit mutation has been centrally confirmed, the patient can be consented
to the trial, the screening/baseline performed and the patient can proceed to
randomization if all inclusion criteria and none of the exclusion criteria have
been met.
A total of 41 patients will be enrolled
The doses of nilotinib will be 400 mg bid every 3 weeks,
The study will use the Simon*s two stage min-max design. The first stage will
consist of 23 patients. The stage 1 decision point will be when all 23 patients
have either reached the 24 Week visit, have discontinued the study, or a
confirmed response to treatment has been
observed. If 2 or fewer responses are observed in stage 1, the trial will be
stopped. The continuous recruitment of patients into stage 2 will be reassessed
if the number of responders in stage 1 is less than the minimum required.
Depending on the pace of patient
screening, a few more patients than the defined stage 1 number may be enrolled
(overrecruitment).
Due to the rarity of the disease and slow patient accrual rate, enrollment will
not be stopped during the analysis of stage 1. The patients recruited beyond
stage 1 will not be included in the decision making analysis at the end of
stage 1. The second stage will include an additional 18 patients. The final
analysis will occur when all 41 patients have reached the 24 Week visit or have
discontinued the study.Patients will follow
the study design shown in Figure 4-1 and have study assessments as described in
Section 7.
Patients who discontinue study drug for any reason other than disease
progression will continue to have tumor assessments on study. Tumor
assessment for these patients will continue until the patient has a documented
disease progression, starts another cancer therapy, or dies.
All patients who discontinue study medication will be followed for 28 days to
evaluate adverse events and serious adverse events.
All patients who withdraw from the study and cease tumor assessment will
befollowed for survival status every 3 months. Follow-up will cease only in
cases of death, withdrawal of consent to follow-up or loss to follow-up.
Intervention
The dose of nilotinib will be 400 mg orally b.i.d. administered continuously.
Dose reduction is required in cases of clinically relevant toxic effects (to
400 mg q.d.) provided criteria for withdrawal from study drug are not met,
which is described in the protocol.
Study burden and risks
Study assessments will be performed at screening, baseline, week 1, week 2,
week 3 and every 3 weeks until the planned total of 94 PFS events have
occurred, whereupon all patients will complete the End of Treatment visit.
Patients withdrawing for any reason will be asked to attend the End of
Treatment visit. Please refer to Table 7-1 and Table 7-2.
Risks:
* Toxicity due to the use of nilotinib
* Reaction to the use of contrast fluid (used for CT scans)
* Side effects of bloodsampling and taking of the biopsies (optional)
Raapopseweg 1
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Raapopseweg 1
6824 DP Arnhem
NL
Listed location countries
Age
Inclusion criteria
1. Histologically confirmed mucosal or acral
2. Presence of a c-Kit mutation of exon 9, 11 or 13, or mutations D820G, N822H, N822K, D820Y, Y822D or Y823D of exon 17, as confirmed by the central laboratory.
3. Stage III unresectable or stage IV disease.
4. The presence of one or more measurable lesions as detected by radiological or photographic methods and assessed according to RECIST. Lesions must have a size of at least 10mm at longest diameter (using a slice thickness of 5 mm) or double the slice thickness to be considered a target lesion. Target lesions should not be selected in previously irradiated fields unless there is clear evidence of progression.
5. WHO performance status 0 - 2.
6. At least 28 days since major surgery prior to straing study drug
7. Age 18 or greater.
8. Patients must have adequate bone marrow and organ function as defined by the following laboratory values:
* Serum potassium within the normal limits or corrected to within normal limits with supplements
* Total calcium (corrected for serum albumin) within the normal limits or corrected to within normal limits with supplements
* Serum magnesium within the normal limits or corrected to within normal limits with supplements
* Serum phosphate within the normal limits or corrected to within normal limits with supplements
* ALT and AST * 2.5 x ULN (upper limit of normal) or * 5.0 x ULN if considered due to tumor.
* Alkaline phosphatase * 2.5 x ULN or * 5.0 x ULN if considered due to tumor.
* Serum bilirubin * 1.5 x ULN.
* Serum creatinine * 1.5 x ULN
* Serum amylase * 1.5 x ULN and serum lipase * 1.5 x ULN.
* Hemoglobin * 9.0 g/dL, absolute neutrophil count *1.5 x 109/L, platelets *100 x 109/L.
9. The capacity to understand the patient information sheet and the ability to provide written informed consent.
10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures.
Exclusion criteria
1. C-Kit mutation of exons 17(except mutations D820G, N822H, N822K, D820Y, Y822D or Y823D) or any other exon not allowed by the inclusion criteria.
2. Patients with c-Kit amplifications without mutations.
3. Patients with any history of brain metastases ,
4. Patients who have had any prior treatment with TKIs,
5. Patients receiving medications or herbal extracts which interfere with nilotinib metabolism which are not discontinued by the time of the baseline visit.
6. Impaired cardiac function, including any one of the following:
* LVEF < 45% or below institutional lower limit of the normal range (which ever is higher) as determined by MUGA scan or echocardiogram.
* Complete left bundle branch block.
* Use of a cardiac pacemaker.
* Congenital long QT syndrome.
* History of or presence of significant ventricular or atrial tachyarrhythmias.
* Clinically significant resting bradycardia (< 50 beats per minute).
* QTc > 450 msec on screening ECG (using the QTcF formula).
* Right bundle branch block plus left anterior hemiblock, bifascicular block.
* Myocardial infarction within 12 months prior to enrollment
* Unstable angina diagnosed or treated during the past 12 months.
* Other clinically significant heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen).
7. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of nilotinib (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or extensive gastric or small bowel resection).
8. History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis.
9. Acute or chronic liver or renal disease considered unrelated to melanoma.
10. Other concurrent severe and/or uncontrolled medical conditions (e.g. uncontrolled diabetes, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol.
11. Patients who are currently receiving treatment with any medications that have a significant potential to prolong the QT interval. See link for list of these medications: http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm.
12. Patients currently receiving therapy with strong CYP3A4 inhibitors. See link for list of these medications: http://medicine.iupui.edu/flockhart/table.htm.
13. Patients receiving therapy with strong CYP3A4 inducers. See link for list of these medications: http://medicine.iupui.edu/flockhart/table.htm.
14. Patients who have received 2 or more prior regimens of systemic anticancer therapy for melanoma.
15. Patients with no evidence of clear progression of disease, either with or without prior systemic anticancer therapy.
16. Patients with less than 12 weeks between their last dose of an anti-CTLA4 agent (i.e. ipilimumab or tremelimumab) and the Screening/Baseline visit.
17. Patients who have received cytotoxic chemotherapy * 4 weeks (6 weeks for nitrosurea or mitomycin-C) prior to starting study drug or who have not recovered from the side effects of such therapy.
18. Patients who have received immunotherapy * 1 week prior to starting study drug or who have not recovered from the side effects of such therapy.
19. Patients who have received any investigational drug * 4 weeks prior to starting study drug or who have not recovered from the side effects of such therapy.
20. Patients who have received wide field radiotherapy * 4 weeks or limited field radiation for palliation * 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
21. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention.
22. Women who are pregnant, breast feeding or adults of reproductive potential not employing an effective method of birth control. Post menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Female patients must agree to employ an effective method of contraception during the study and for up to three months following discontinuation from the study. Effective methods of contraception are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly.
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 | EUCTR2009-015514-21-NL |
| ClinicalTrials.gov | NCT01028222 |
| CCMO | NL38641.091.11 |