Phase I part To determine the recommended safe dosing for the combination of chemoradiation with gemcitabine plus panitumumab in patients with inoperable locally advanced pancreatic cancer.Phase II part 1) To investigate the proportion of patients…
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary objective Phase I
1 To determine the recommended safe dosing for the combination of
chemoradiation with gemcitabine plus panitumumab in patients with inoperable
locally advanced pancreatic cancer.
Primary objectives Phase II
1) To investigate the proportion of patients with inoperable locally advanced
pancreatic cancer receiving chemoradiation with gemcitabine plus panitumumab as
first line treatment, that is alive and progression-free at 7 months.
2) To evaluate the safety and tolerability for the combination of
chemoradiation with gemcitabine, plus panitumumab in patients with inoperable
locally advanced pancreatic cancer.
Secondary outcome
Phase I & II part:
1) To assess early signs of clinical activity of the combination of
chemoradiation with gemcitabine plus panitumumab in patients with inoperable
locally advanced pancreatic cancer.
2) To assess the clinical response rate of the combination of chemoradiation
with gemcitabine plus panitumumab in patients with inoperable locally advanced
pancreatic cancer.
3) To assess time-to-progression (TTP) and overall survival amongst patients
with inoperable locally advanced pancreatic cancer receiving chemoradiation
with gemcitabine plus panitumumab as first line treatment.
Background summary
Based on the radiotherapy potentiating effects of both gemcitabine and
EGFR-inhibitors (independent of K-ras mutation status), and the non-overlapping
toxicity profiles of gemcitabine and panitumumab, we aim to evaluate the
combination of radiotherapy plus gemcitabine and panitumumab in patients with
locally advanced inoperable pancreatic cancer in a phase I-II feasibility study
aiming for an increase in the PFS. Based on historical data of patients with
locally advanced, inoperable, pancreatic cancer treated with chemoradiation, we
aim to increase the number of patients who are cancer progression free at 7
months from the historical value of 50% to 70% with combination treatment of
chemoradiation with gemcitabine plus panitumumab. In addition to efficacy, we
will evaluate treatment toxicity to determine whether this combination strategy
is feasible and safe.
Study objective
Phase I part
To determine the recommended safe dosing for the combination of chemoradiation
with gemcitabine plus panitumumab in patients with inoperable locally advanced
pancreatic cancer.
Phase II part
1) To investigate the proportion of patients with inoperable locally advanced
pancreatic cancer receiving chemoradiation with gemcitabine plus panitumumab as
first line treatment, that is progression-free at 7 months.
2) To evaluate the safety and tolerability for the combination of
chemoradiation with gemcitabine plus panitumumab in patients with inoperable
locally advanced pancreatic cancer.
Secondary Aims
1) To assess early signs of clinical activity of the combination of
chemoradiation with gemcitabine plus panitumumab in patients with inoperable
locally advanced pancreatic cancer.*
2) To assess the clinical response rate of the combination of chemoradiation
with gemcitabine plus panitumumab in patients with inoperable locally advanced
pancreatic cancer.
3) To assess time-to-progression (TTP) and overall survival amongst patients
with inoperable locally advanced pancreatic cancer receiving chemoradiation
with gemcitabine plus panitumumab as first line treatment.
Exploratory aim
To explore the activity of combination chemoradiation with gemcitabine plus
panitumumab in relation to response to therapy and:
a) the prevalence of mutant versus wild-type K-ras and B-raf.
b) pre-treatment kinome tumor profiles and serum proteomic profiles.
Study design
This is a phase I/II, multi-center dose escalation study of panitumumab in
combination with gemcitabine and radiotherapy in patients with inoperable
locally advanced pancreatic cancer. The phase I study will be performed in the
VU medical center in Amsterdam. For the phase II part of the study two
additional sites will be involved in the Netherlands.
Phase I part:
Patients will be enrolled in cohorts of 3 per dose level. The first 3 patients
enrolled will be assigned to dose level 1. If there are no dose-limiting
toxicities (DLTs) experienced by the first 3 patients in a cohort during the
first 43 days after the first study treatment, additional patients will be
entered in the next dose level. Entry of patients into the expansion cohort
will not occur until at least 43 days after the last patient in the escalation
phase received his first study treatment. At the final dose level recommended
for the phase II study a minimum of 6 patients will be treated.
Intra-individual dose escalation is not permitted in order to allow
determination of any possible cumulative effect and to evaluate the inherent
toxicity of the regimen at any given dose level and before starting with the
next cohort.
Phase II part:
Up to approximately 56 patients will be treated at the MTD level of panitumumab
as established in the phase I part of the study.
Based on historic data of patients with pancreatic cancer treated with
gemcitabine based chemoradiation, we aim to increase the number of patients who
are alive and cancer progression free at 7 months from the historical value of
50% to 70% with combination treatment of chemoradiation plus panitumumab. In
addition, we consider this increase meaningfull as long as the combination
treatment does not increase combination treatment related toxicity grade 3 or 4
in * 30% of patients.
Interim analysisfor 7 months progression free survival and toxicity:
An interim analysis (IA) will be performed after treatment of a total of 24
patients that reached 7 months progression free survival or did progress within
the first 7 months. If the number of patients progression free (PF) at 7 months
is *12 then the study will terminate due to lack of response. In addition, at
the same IA of 24 patients, the number of patients with combination treatment
related grade 3/4 toxicity will be analyzed and if this number is 12 or higher
patients the study will be terminated because of unacceptable toxicity.
Enrolment of new patients (more than 24) up to 30 will continue as long as no
IA can be performed due to rapid inclusion of patients within the first 7
months after start of the phase II part.
Intervention
Phase I part:
Cohorts of 3-6 patients will be treated with escalating doses of panitumumab to
determine the recommended safe dosing for the combination of chemoradiation
with gemcitabine plus panitumumab in patients with inoperable locally advanced
pancreatic cancer.
Phase II part:
Up to approximately 56 patients will be treated at the MTD level of panitumumab
(in combination with gemcitabine and radiation therapy) as established in the
phase I part of the study.
Study burden and risks
Possible side effects of gemcitabine: nausea and vomiting, low lymphocyte and
erythrocyte count. Patients can suffer from influenza-like syndroms like fever,
headache, backpain, chills, muscle pain and fatigue.
The most common side effects of panitumumab are skin rash and diarrhea (mild),
fatigue, nausea, infusion reactions (influenza-like syndroms, allergy),
shortness of breath, low magnesium in blood and keratitis.
The possible side effects of radiotherapy are: fatigue, nausea, loss of
apetite, weight loss and diarrhea.
De Boelelaan 1117
1081 HV
NL
De Boelelaan 1117
1081 HV
NL
Listed location countries
Age
Inclusion criteria
1. Histological or cytological confirmed pancreatic cancer.
2. Not eligible for curative resection.
3. No distant metastases present.
4. Previously untreated with chemotherapy and anti-cancer biologicals for current malignancy.
5. No other current malignant disease.
6. Measurable or evaluable disease as defined by RECIST 1.1 criteria.
7. Performance status 0*2 Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Scale.
8. Age * 18 years.
9. Adequate haematological and biological functions:
* Bone marrow function:
a. Neutrophils * 1.5 x 10E9/L
b. Platelets * 100 x 10E9/L
c. Hb * 10 g/dL (<= 6 mmol/L)
* Hepatic function:
a. AST/ALT and alkaline phosphatase (ALP) * 2.5 x institutional upper limit of normal (ULN)
b. Bilirubin * 1.5 times institutional ULN
* Renal function:
Serum creatinine * 1.5 times institutional ULN.
* Metabolic Function:
a. Magnesium * lower limit of normal
b. Calcium * lower limit of normal.
10. No imminent bowel obstruction.
11. No active bleeding.
12. No uncontrolled infection.
13. Patients with reproductive potential must use effective contraception. Female patients must have a negative pregnancy test.
14. Signed informed consent.
Exclusion criteria
1. Participation in another therapeutic clinical study within 30 days of enrollment or during this clinical study.
2. No adequate radiation therapy possible: based on the opinion of the radiation oncologist when radiation therapy cannot be performed because radiation field is too large (PTV volume too large or OAR too high)
3. History of allergic reactions to gemcitabine or antibody treatment.
4. Presence of any serious concomitant systemic disorders incompatible with the clinical study (e.g. uncontrolled inter-current illness including ongoing or active infection, uncontrolled hypertension).
5. Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) within 1 year before enrolment/randomization
6. History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan.
7. Presence of any significant central nervous system or psychiatric disorder(s) that would hamper the patient*s compliance.
8. Pregnant or breastfeeding women.
9. Absence of adequate contraception for both male and female fertile patients for the duration of the study; and also for six months after last treatment.
10. Known positive status for HIV and/or hepatitis B or C.
11. Any reason why, in the investigator*s opinion, the patient should not participate in the study.
12. Drug or alcohol abuse.
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 | EUCTR2010-018327-26-NL |
| CCMO | NL30918.029.10 |