Primary objective *To determine Maximum Tolerated Dose (MTD) of TH-302 combined with chemoradiotherapy (23 x1.8 Gy in combination with Carboplatinum and Paclitaxel) in patients with distal esophageal or esophago-gastric junction adenocarcinoma, and…
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Incidence of
*Uncommon grade 3 or higher non-hematological toxicity (according to CTCAE v4.0
see appendix) except for esofagitis where grade III toxicity is already an
acceptable toxicity in up to 10% of patients. We accept in this phase I study a
grade III esophagitis of 50%. We accept grade 3 nausea and emesis unless
standard anti-emetics have been used.
*Grade 4 or higher hematological toxicity (according to CTCAE v4.0)
*Grade 4 or higher postoperative toxicity within 30 days post-surgery according
to the Clavien-Dindo classification . For anastomic leakage we accept a grade
IV of 50% and for cardiorespiratory complications up to 30% grade IV will be
*Any grade 2 or higher non-hematologic toxicity except for esophagitis that
does not resolve to grade 0 or 1 toxicity by the start of the next cycle of
chemotherapy which, in judgment of the investigator or sponsor is considered a
DLT
*Inability to begin the next cycle of chemotherapy of treatment within two
weeks of the last dose due to unresolved toxicity
Secondary outcome
*Presence of hypoxia response based on quantifiable changes in hypoxia
calculated from HX4 images at baseline compared to those at first
administration TH-302 (before chemoradiotherapy).
*Presence of anti-tumor activity measured by the rate of pathological Complete
Remission (pCR), histopathologic negative circumferential resection margin
(CRM) rate, local and distance recurrence rate, progression free and overall
survival, metabolic response one month after treatment.
*Correlation between HX4 PET/CT-scans and serum biomarker expression
Background summary
Combining TH-302 with chemo-radiotherapy will lead to:
*Direct cytotoxic effect of TH-302 on hypoxic cells of the primary tumor
without enhancing normal tissue toxicity.
*Increase the sensitivity of the primary tumour to chemo-radiotherapy by
decreasing the hypoxic fraction.
*A bystander cytotoxic effect of TH-302 on normoxic cells adjacent to hypoxic
cells of the primary tumor.
*A potential cytotoxic effect on micrometastasis.
Study objective
Primary objective
*To determine Maximum Tolerated Dose (MTD) of TH-302 combined with
chemoradiotherapy (23 x1.8 Gy in combination with Carboplatinum and Paclitaxel)
in patients with distal esophageal or esophago-gastric junction adenocarcinoma,
and consequently find the recommended Phase II dose (RP2D).
Secondary objective
*To explore the prognostic and predictive value on outcome of the repeated
hypoxia PET/CT-scan at baseline and after administration of TH-302 (before
start of RCT) .
*To determine presence of anti-tumor activity with TH-302 administration.
*To explore the relationship between tumour hypoxia detected by the HX4
PET/CT-scans and serum biomarker expression: HIF-1*, VEGF, CAIX, CD44,
microRNA-210 and osteopontin expression
Study design
Open-label, single-center phase 1 study of an investigational agent TH-302 and
standard chemoradiotherapy with a 3+3 dose escalation design through 3 dose
levels.
Intervention
3 cohorts of patients will receive TH-302 in escalating doses during standard
chemo-radiotherapy Extra patients can be added to a cohort in case of dose
limiting toxicity, resulting in a maximum of 6 patients per dose level. Each
patient included will have HX4 imaging before (d1) and after the first dosage
of TH-302 (d8). TH-302, available for intravenous (IV) infusion, will be
administered one week before start of chemoradiotherapy (d4), continued on a
weekly basis for a total of 6 doses. TH-302 should be administered prior to
Carboplatinum/paclictaxel and prior to radiotherapy. The administration of
chemotherapy should start 2 to 4 hours after completion of the TH-302 infusion.
During phase I, the initial dose level of TH-302 will be 120 mg/m2 with
infusion over 30 to 60 minutes. The following dose escalations will be
implemented: level 2 = 240 mg/m2 and level 3 = 340 mg/m2. In case of toxicity
at the first dose level, inclusion in level -1 (60 mg/m2) is planned.
Intermediate doses may be explored based on the cumulative safety data.
In combination with the investigating drug, the standard regimen of
chemotherapy will be administered: Paclitaxel (50 mg/m2) and Carboplatin (AUC =
2 mg/ml/min) will be given by intravenous infusion weekly for a total of 5
doses starting on the day 11. Chemotherapy will be combined with fractionated
irradiation (RapidArc) to a total dose of 41.4Gy administered in 23 fractions
of 1.8Gy 1, starting the first day of the first cycle of chemotherapy (shown in
figure 1).
Study burden and risks
Patients participating in the trial will be subjected to a baseline HX4 PET/CT
scan before the start of any treatment. One week before the start of the
standard chemoradiotherapy, patients will receive the first intravenous
administration of TH-302 on an out-patient base, followed by HX4 imaging four
days later. The blood samples for the hypoxia biomarker expression will be
collected on the same days as the HX4 scans. During the standard
chemoradiotherapy treatment, TH-302 will be administered 2-4 hours prior to the
chemotherapy (Carboplatinum/Paclitaxel) and no additional hospital visit is
required. So in conclusion, we foresee three additional hospital visits (two at
MAASTRO Clinic and one at Atrium-Orbis Medical Center):
*Day 1 (Friday): Hx4 imaging (MAASTRO clinic)
*Day 4 (Monday): First dosage TH-302 IV (Atrium/Orbis)
*Day 8 (Friday): Hx4 imaging (MAASTRO clinic)
The potential benefit of this combined treatment is the overcoming of the
resistance to chemoradiation in hypoxic tumor regions, by administration of the
drug TH-302. TH-302 is expected to have little broad systemic toxicity due to
its selective activation under hypoxic conditions. Prognosis of patients with
esophageal cancer remains dismal, especially for non-responders to
chemoradiotherapy (5-year overall survival varying from 10 to 30%). There is
evidence that complete responders to chemoradiotherapy have better outcome, so
every gain in treatment effect is worthwile.
Dr. Tanslaan 12
6229 ET Maastricht
NL
Dr. Tanslaan 12
6229 ET Maastricht
NL
Listed location countries
Age
Inclusion criteria
*Histologically proven adenocarcinoma of the esophagus
*Age>18 years
*UICC T2-4 N0-2 M0, potentially resectable disease
*Patient discussed at tumour board (multidisciplinary team meeting)
*No evident tumor invasion in nearby regions like aorta, trachea
*WHO performance status 0-2
*Less than 10 % weight loss the last 6 months
*Laboratory requirements within 7 days prior to enrollment (start chemoradiotherapy):
Haemotology: haemoglobin >10g/dl, absolute neutrophils * 1.5 x 109/L,platelets * 100x109/L
Biochemistry:bilirubin within normal limits, AST(SGOT)/ALT (SGPT) * 2.5 institutional upper limit, Creatinine clearance * 60 ml/min.
*Willing and able to comply with the study prescriptions
*No history of prior thoracic radiotherapy
*No severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the investigator any physiological state leading to hypoxemia
*Women should not be pregnant or lactating
*No known infection with HIV, hepatitis B or C or any other active infection
*Normal ECG with careful evaluation of QT/QTc
*Have given written informed consent before patient registration
Exclusion criteria
*Recent (< 3 months) severe cardiac disease (arrhythmia, congestive heart failure, infarction)
*Patients with difficult peripheral intravenous access
*History of prior thoracic radiotherapy
*Severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the investigator any physiological state leading to hypoxemia
*Women who are pregnant or lactating
*Known infection with HIV, hepatitis B or C or any other active infection
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 |
|---|---|
| Other | 14-27-03/09 |
| EudraCT | EUCTR2014-004700-30-NL |
| CCMO | NL52134.096.15 |