To determine the feasibility, toxicity and safety of anti-CEA x anti hapten bispecific antibodies (TF2) and Lu-177-labelled di-HSG-DOTA peptide (IMP-288) in patients with advanced colorectal carcinoma.
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Toxicity, as defined in NCI Common Terminology Criteria for Adverse Events
(CTCAE v 3.0)
Secondary outcome
Pharmacokinetics and biodistribution of bispecific antibody TF2 and
Lu-177-labeled IMP-288 peptide;
Tumor response using RECIST criteria
Background summary
Radioimmunotherpay is an effective therapy for hematologic malignicies. Two
radiolabeled anti-CD20 antibodies are registered for Non-Hodgkin*s Lymphoma.
The treatment of solid tumors with the same technique is suboptimal, with a low
percentage of the injected dose that will reach the tumor, and signicifant bone
marrow toxicity. One of the methods to improve the efficacy is pretargeting
with bispecific antibodies, that are anti-tumor as well as anti-hapten. First
the antibody will be (intravenously) administered, and after its clearance from
the circulation the radiolabeled hapten will be given. For colorectal tumors
the humanized anti-CEA x anti-HSG bispecific antibody, TF2, and the di-HSG-DOTA
peptide, IMP-288 are developed. In preclinical studies it is shown that the
pretargeting system can bring higher activity doses to the tumor. A therapeutic
study in mice has shown superior therapeutic effects compared to
(non-pretargeted) radioimmunotherapy. No clinical studies have been performed
with TF2 and/or IMP-288.
Study objective
To determine the feasibility, toxicity and safety of anti-CEA x anti hapten
bispecific antibodies (TF2) and Lu-177-labelled di-HSG-DOTA peptide (IMP-288)
in patients with advanced colorectal carcinoma.
Study design
Phase I clinical trial
Intervention
All patients receive intravenously TF2 and radiolabeled IMP-288. The dose of
IMP-288 will be the same for each patient. Variation in the TF2 dose and the
interval between TF2 and IMP-288 will be executed in four cohorts. Cohort 1
will receive 150 mg TF2, and five days later IMP-288. Cohort 2: 300 mg, 5-days
interval; cohort 3: 300 mg, 3-days interval; cohort 4: 600 mg, 5-days interval.
Two weeks prior to administration of Lu-177-IMP288, for each individual patient
dosimetric calculations will be performed with a low diagnostic dose of
In-111-IMP288. Patients receive TF2 and IMP288 according to the dosing schedule
of their cohort. With gamma camera imaging the Lu-177-IMP288 dose will be
calculated that will result in a safe radiation dose: 15 Gy for the kidneys and
125 cGy for the bone marrow. In previous clinical trials, with much higher
radiation doses that did not exceed 27 Gy for the kidneys and 125 cGy for the
bone marrow, rarely long term renal failure or irreversible bone marrow
toxicity was observed.
This individual total activity dose Lu-177 will be administered in four
successive cycles, each with a quarter of the total dose. The maximal Lu-177
dose per cycle is 3.7 GBq in cohort 1, and 7.4 GBq in the next cohorts.
After each therapeutic cycle of Lu, the cumulative radiation dose to the bone
marrow and kidneys will be calculated, to evaluate if this does not exceed the
maximum radiation dose.
The minimal period of time for recovery and before to start with the next cycle
is eight weeks.
Study burden and risks
Potential risks of this therapy are: reversible bone marrow toxicity, renal
toxicity or allergic/infusion reaction on TF2.
The burden for the participating patients consists of frequent visits to the
hospital, for venapuncture and gamma camera imaging. These are performed for
farmacokinetics, biodistribution and monitoring of potential toxicity. A short
admission in an isolated room after the infusion of IMP-288-Lu-177 will prevent
radiation to the surroundings. During and till 6-8 hours after TF2 infusion,
patients will be guarded by medical and nursing staff, their vital signs will
be checked and they will be observed for adverse reactions or infusion
reactions.
Geert Grooteplein-Zuid 10
6525 GA Nijmegen
NL
Geert Grooteplein-Zuid 10
6525 GA Nijmegen
NL
Listed location countries
Age
Inclusion criteria
•Patients with CEA expressing advanced colorectal tumors for which no standard treatment is available
•WHO performance status: 0 or 1
•Having normal hematological funtion:
• Neutrophils > 1.5 x 109/l
• Platelet count > 150 x 109/l, without transfusion
• Hemoglobin > 6 mmol/l
• Total bilirubin < 2 x upper limit of normal (ULN)
• ASAT, ALAT < 3 x ULN
• Serum creatinine < 2 x ULN
•Cockcroft clearance > 50 ml/min
•Negative pregnancy test for women of child¬bearing potential (urine or serum)
•Age over 18 years
•Ability to provide written informed consent
Exclusion criteria
•Known metastases to the brain
•Chemotherapy, external beam radiation or immunotherapy within 4 weeks prior to study. Limited field external beam radiotherapy to prevent pathological fractures is allowed, when unirradiated, evaluable lesions elsewhere are present.
•Prior angiogenesis inhibitors within 4 weeks; bevacizumab within 8 weeks
•Cardiac disease with New York Heart Association classification of III or IV
•Patients who are pregnant, nursing or of reproductive potential and are not practicing an effective method of contraception
•Any unrelated illness, e.g. active infection, inflammation, medical condition or laboratory abnormalities, which in the judgement of the investigator will significantly affect patients* clinical status
•Life expectancy shorter than 6 months.
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 | EUCTR2008-004003-55-NL |
| CCMO | NL23625.091.08 |