A Phase 1 interventional study of Avastin and Oxaliplatin in Colorectal Cancer, sponsored by Hoffmann-La Roche. Completed at 3 sites in Canada. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2016-03-04.
Sponsored by Hoffmann-La Roche · Phase 1, Interventional, and Treatment
This single arm study will investigate possible pharmacokinetic interactions between Xeloda and oxaliplatin, and assess whether the pharmacokinetics of Xeloda and/or oxaliplatin is influenced by the addition of Avastin. All subjects will provide samples for pharmacokinetic analysis during the first 3 cycles of treatment. In cycles 1 and 2 patients will receive a treatment regimen containing Xeloda (1000mg/m2 bid) and oxaliplatin (130mg/m2 iv) and in cycle 3 Avastin (7.5mg/kg iv) will be added to the regimen. The anticipated time on study treatment is 3-12 months, and the target sample size is \<100 individuals.
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Exclusion Criteria:
Drug: Avastin · Drug: Oxaliplatin · Drug: capecitabine [Xeloda]
7.5mg/kg iv (cycle 3 only)
130mg/m2 iv (cycles 1, 2 and 3)
1000mg/m2 po bid (cycles 1, 2 and 3)
Area Under The Plasma Concentration-Time Curve From Zero To Infinity (AUC0-Inf) of 5'-Deoxy-5-fluorouridine 5'-(DFUR)
AUC0-infinity represents the area under the concentration-time curve of the analyte (5'-DFUR) in plasma over the time interval from 0 extrapolated to infinity. The analyte 5'-DFUR, the direct precursor of 5-fluorouracil (5-FU), is considered to be the most important metabolite of capecitabine in plasma. The unit of measure was nanograms per millilitre per hour (ng/mL \* hr).
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours post the dose.
AUC0-inf for Free Platinum
AUC0-infinity represents the area under the concentration-time curve of the analyte (free platinum) in plasma over the time interval from 0 extrapolated to infinity. AUC0-inf for free platinum was calculated for each participant from the concentration-data obtained on Days 2 to 5 of Cycle 1, and Days 1 to 4 for Cycle 2 and 3. Free platinum is not bound to plasma proteins and is considered to be the most clinically significant measure of pharmacological and toxicological activity.
Time frame: Predose , 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 and 72 hours from the beginning of the 2 hour oxaliplatin infusion on Days 2 to 5 of Cycle 1, and Days 1 to 4 for Cycle 2 and 3.
AUC (0-infinity) of Capecitabine and Its Metabolites (5'-DFCR, 5-FU, and FBAL)
AUC0-infinity represents the area under the concentration-time curve of the analytes (5'-DFCR, 5-FU, and FBAL) in plasma over the time interval from 0 extrapolated to infinity. After oral administration, capecitabine is first metabolized in the liver to 5'-deoxy-5-fluorocytidine (5'-DFCR), which is then converted to 5'-DFUR, and then catalytically activated to 5-FU.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours post the dose
AUC0-last of Capecitabine and Its Metabolites (5'-DFUR, 5'-DFCR, 5 FU, and FBAL)
Area under the plasma concentration-time curve from time zero to the time of the last measurable plasma concentration time point of capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5 FU, and FBAL).
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours post the dose
Maximum Plasma Concentration (Cmax) of Capecitabine and Its Metabolites (5'-DFUR, 5'-DFCR, 5 FU, and FBAL)
Cmax is defined as maximum observed analyte concentration of capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5 FU, and FBAL)
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours post the dose
Elimination Half-life Period (t1/2 Beta) of Capecitabine and Its Metabolites (5'-DFUR , 5'-DFCR, 5 FU, and FBAL)
t1/2 Beta is the time measured for the plasma concentration to decrease by 1 half to its original concentration of capecitabine and its metabolites (5'-DFUR , 5'-DFCR, 5 FU, and FBAL)
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours post the dose
AUC0-infinity for Total Platinum
AUC0-infinity represents the area under the concentration-time curve of the analyte (total platinum) in plasma over the time interval from 0 extrapolated to infinity.
Time frame: Pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 and 72 hours from the beginning of the two hour oxaliplatin infusion on Days 2 to 5 of Cycle 1, and Days 1 to 4 for Cycle 2 and 3
AUC0-last of Total And Free Platinum
Area under the plasma concentration-time curve from time zero to the time of the last measurable plasma concentration time point of Total And Free Platinum.
Time frame: pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 and 72 hours from the beginning of the two hour oxaliplatin infusion on Days 2 to 5 of Cycle 1, and Days 1 to 4 for Cycle 2 and 3.
Cmax of Total And Free Platinum
Cmax is defined as maximum observed analyte concentration of Total And Free Platinum.
Time frame: Pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 and 72 hours from the beginning of the two hour oxaliplatin infusion on Days 2 to 5 of Cycle 1, and Days 1 to 4 for Cycle 2 and 3.
T1/2 Beta of Total And Free Platinum
T1/2 beta is the time measured for the plasma concentration to decrease by 1 half to its original concentration of total and free platinum.
Time frame: Pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 and 72 hours from the beginning of the two hour oxaliplatin infusion on Days 2 to 5 of Cycle 1, and Days 1 to 4 for Cycle 2 and 3
Volume of Distribution at Steady State (VSS) of Total And Free Platinum
VSS is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state.
Time frame: Pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 and 72 hours
Clearance of Total And Free Platinum
CL is a calculation of the rate at which a drug is removed from the body via renal, hepatic and other clearance pathways, expressed as volume (milliliters) per unit of time (hour).
Time frame: Pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 and 72 hours from the beginning of the two hour oxaliplatin infusion on Days 2 to 5 of Cycle 1, and Days 1 to 4 for Cycle 2 and 3
Number Of Participants With Adverse Events (AEs)
An adverse event is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product. This includes any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Pre-existing conditions which worsened during the study were also to be reported as AEs.
Time frame: Approximately 3 Years (up to 28 days after the last intake of study medication)
Marked Laboratory Abnormalities
Number of participants with marked laboratory abnormalities (hematology, coagulation, liver function, renal function, protein, electrolytes, miscellaneous).
Time frame: Up to 28 days after last chemotherapy administration
A total of 36 participants were enrolled in this study at three sites in Canada between 8 August 2005 and 24 April 2008.
| Milestone | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| Started | 36 |
| Completed | 7 |
| Not completed | 29 |
| Withdrew: Adverse event | 8 |
| Withdrew: Withdrawal by subject | 2 |
| Withdrew: Insufficient therapeutic response | 13 |
| Withdrew: Progression | 1 |
| Withdrew: Surgery | 4 |
| Withdrew: Break from chemotherapy | 1 |
AUC0-infinity represents the area under the concentration-time curve of the analyte (5'-DFUR) in plasma over the time interval from 0 extrapolated to infinity. The analyte 5'-DFUR, the direct precursor of 5-fluorouracil (5-FU), is considered to be the most important metabolite of capecitabine in plasma. The unit of measure was nanograms per millilitre per hour (ng/mL \* hr).
| ng/mL*hr | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| Cycle 1, Day 1 | 13605 ± 33 |
| Cycle 2, Day 1 | 12177 ± 27 |
| Cycle 3, Day 1 | 11817 ± 38 |
AUC0-infinity represents the area under the concentration-time curve of the analyte (free platinum) in plasma over the time interval from 0 extrapolated to infinity. AUC0-inf for free platinum was calculated for each participant from the concentration-data obtained on Days 2 to 5 of Cycle 1, and Days 1 to 4 for Cycle 2 and 3. Free platinum is not bound to plasma proteins and is considered to be the most clinically significant measure of pharmacological and toxicological activity.
| ng/mL * hr | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| Cycle 1, Day 2 | 10069 ± 23 |
| Cycle 2 , Day 1 | 10537 ± 24 |
| Cycle 3, Day 1. | 10225 ± 23 |
AUC0-infinity represents the area under the concentration-time curve of the analytes (5'-DFCR, 5-FU, and FBAL) in plasma over the time interval from 0 extrapolated to infinity. After oral administration, capecitabine is first metabolized in the liver to 5'-deoxy-5-fluorocytidine (5'-DFCR), which is then converted to 5'-DFUR, and then catalytically activated to 5-FU.
| ng/mL*hr | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| Capcetabine , Cycle 1, Day 1 | 5217 ± 57 |
| Capcetabine , Cycle 2, Day 1 | 5299 ± 54 |
| Capcetabine , Cycle 3, Day 1 | 6130 ± 68 |
| 5'-DFCR , Cycle 1, Day 1 | 7630 ± 76 |
| 5'-DFCR , Cycle 2, Day 1 | 6409 ± 47 |
| 5'-DFCR, Cylce 3, Day 1 | 7989 ± 52 |
| 5-FU , Cycle 1, Day 1 | 437 ± 92 |
| 5-FU , Cycle 2, Day 1 | 355 ± 50 |
| 5-FU , Cycle 3, Day 1 | 343 ± 86 |
| FBAL , Cycle 1, Day 1 | 17904 ± 27 |
| FBAL , Cycle 2, Day 1 | 17413 ± 26 |
| FBAL , Cycle 3, Day 1 | 17356 ± 34 |
Area under the plasma concentration-time curve from time zero to the time of the last measurable plasma concentration time point of capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5 FU, and FBAL).
| ng/mL*hr | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| 5' DFUR , Cycle 1, Day 1 | 13503 ± 33 |
| 5' DFUR, Cycle 2 , Day 1 | 12057 ± 28 |
| 5' DFUR, Cycle 3, Day 1 | 11618 ± 38 |
| Capecitabine, Cycle 1, Day 1 | 5201 ± 57 |
| Capecitabine, Cycle 2, Day 1 | 5273 ± 54 |
| Capecitabine, Cycle 3, Day 1 | 6093 ± 68 |
| 5'-DFCR, Cycle 1, Day 1 | 6150 ± 80 |
| 5'-DFCR, Cycle 2 , Day 1 | 6378 ± 47 |
| 5'-DFCR, Cycle 3, Day 1 | 7909 ± 52 |
| 5-FU, Cycle 1, Day 1 | 433 ± 92 |
| 5-FU, Cycle 2, Day 1 | 350 ± 51 |
| 5-FU, Cycle 3, Day 1 | 336 ± 84 |
| FBAL, Cycle 1, Day 1 | 16773 ± 26 |
| FBAL, Cycle 2, Day 1 | 15992 ± 26 |
| FBAL, Cycle 3, Day 1 | 14947 ± 31 |
Cmax is defined as maximum observed analyte concentration of capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5 FU, and FBAL)
| ng/mL | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| 5'-DFUR, Cycle 1, Day 1 | 8847 ± 48 |
| 5'-DFUR , Cycle 2, Day 1 | 6545 ± 48 |
| 5'-DFUR , Cycle 3, Day 1 | 5693 ± 54 |
| Capecitabine, Cycle 1, Day 1 | 4930 ± 72 |
| Capecitabine, Cycle 2, Day 1 | 4065 ± 73 |
| Capecitabine, Cycle 3, Day 1 | 4167 ± 81 |
| 5' DFCR, Cycle 1, Day 1 | 3902 ± 78 |
| 5' DFCR, Cycle 2, Day 1 | 3407 ± 66 |
| 5' DFCR , Cycle 3, Day 1 | 3747 ± 69 |
| 5-FU, Cycle 1 , Day 1 | 292 ± 63 |
| 5-FU, Cycle 2, Day 1 | 216 ± 63 |
| 5-FU, Cycle 3, Day 1 | 168 ± 83 |
| FBAL, Cycle 1, Day 1 | 3970 ± 19 |
| FBAL, Cycle 2, Day 1 | 3627 ± 27 |
| FBAL, Cycle 3, Day 1 | 3292 ± 34 |
t1/2 Beta is the time measured for the plasma concentration to decrease by 1 half to its original concentration of capecitabine and its metabolites (5'-DFUR , 5'-DFCR, 5 FU, and FBAL)
| hour | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| 5' DFUR; Cycle 1, Day 1 | 0.65 ± 19 |
| 5' DFUR, Cycle 2 , Day 1 | 0.64 ± 49 |
| 5' DFUR, Cycle 3, Day 1 | 0.75 ± 39 |
| Capecitabine, Cycle 1, Day 1 | 0.37 ± 52 |
| Capecitabine, Cycle 2, Day 1 | 0.51 ± 55 |
| Capecitabine, Cycle 3, Day 1 | 0.56 ± 42 |
| 5'-DFCR, Cycle 1, Day 1 | 0.71 ± 33 |
| 5'-DFCR, Cycle 2 , Day 1 | 0.75 ± 32 |
| 5'-DFCR, Cycle 3, Day 1 | 0.79 ± 24 |
| 5-FU, Cycle 1, Day 1 | 0.61 ± 20 |
| 5-FU, Cycle 2, Day 1 | 0.67 ± 61 |
| 5-FU, Cycle 3, Day 1 | 0.71 ± 31 |
| FBAL, Cycle 1, Day 1 | 2.77 ± 19 |
| FBAL, Cycle 2, Day 1 | 2.68 ± 26 |
| FBAL, Cycle 3, Day 1 | 2.64 ± 33 |
AUC0-infinity represents the area under the concentration-time curve of the analyte (total platinum) in plasma over the time interval from 0 extrapolated to infinity.
| ng/mL* hr | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| Cycle 1, Day 2 | 139329 ± 24 |
| Cycle 2, Day 1 | 167610 ± 17 |
| Cycle 3, Day 1 | 186268 ± 21 |
Area under the plasma concentration-time curve from time zero to the time of the last measurable plasma concentration time point of Total And Free Platinum.
| ng/mL* hr | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| Total Platinum: Cycle 1, Day 2 | 85406 ± 20 |
| Total Platinum: Cycle 2, Day 1 | 97083 ± 12 |
| Total Platinum: Cycle 3, Day 1 | 97011 ± 17 |
| Free Platinum: Cycle 1, Day 2 | 9399 ± 24 |
| Free Platinum: Cycle 2, Day 1 | 9818 ± 25 |
| Free Platinum: Cycle 3, Day 1 | 9604 ± 22 |
Cmax is defined as maximum observed analyte concentration of Total And Free Platinum.
| ng/mL | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| Total Platinum: Cycle 1, Day 2 | 3652 ± 14 |
| Total Platinum: Cycle 2, Day 1 | 3741 ± 19 |
| Total Platinum: Cycle 3, Day 1 | 3706 ± 21 |
| Free Platinum: Cycle 1, Day 2 | 1818 ± 27 |
| Free Platinum: Cycle 2, Day 1 | 1840 ± 36 |
| Free Platinum: Cycle 3, Day 1 | 1813 ± 30 |
T1/2 beta is the time measured for the plasma concentration to decrease by 1 half to its original concentration of total and free platinum.
| hour | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| Total Platinum: Cycle 1, Day 2 | 48.70 ± 30 |
| Total Platinum: Cycle 2, Day 1 | 55.73 ± 24 |
| Total Platinum: Cycle 3, Day 1 | 67.28 ± 26 |
| Free Platinum: Cycle 1, Day 2 | 17.64 ± 10 |
| Free Platinum: Cycle 2, Day 1 | 18.41 ± 9 |
| Free Platinum: Cycle 3, Day 1 | 18.47 ± 10.90 |
VSS is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state.
| mL | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| Total Platinum: Cycle 1, Day 2 | 109007 ± 23 |
| Total Platinum: Cycle 2, Day 1 | 105097 ± 21 |
| Total Platinum: Cycle 3, Day 1 | 112141 ± 21 |
| Free Platinum: Cycle 1, Day 2 | 387158 ± 23 |
| Free Platinum: Cycle 2, Day 1 | 389193 ± 29 |
| Free Platinum: Cycle 3, Day 1 | 401040 ± 24 |
CL is a calculation of the rate at which a drug is removed from the body via renal, hepatic and other clearance pathways, expressed as volume (milliliters) per unit of time (hour).
| mL/Hr | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| Total Platinum: Cycle 1, Day 2 | 1603 ± 78 |
| Total Platinum: Cycle 2, Day 1 | 1331 ± 22 |
| Total Platinum: Cycle 3, Day 1 | 1198 ± 25 |
| Free Platinum: Cycle 1, Day 2 | 22183 ± 23 |
| Free Platinum: Cycle 2, Day 1 | 21176 ± 26 |
| Free Platinum: Cycle 3, Day 1 | 21823 ± 23 |
An adverse event is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product. This includes any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Pre-existing conditions which worsened during the study were also to be reported as AEs.
| Participants | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| Any AE | 36 |
| Any SAE | 16 |
Number of participants with marked laboratory abnormalities (hematology, coagulation, liver function, renal function, protein, electrolytes, miscellaneous).
| Participants | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| Hematocrit - high | 2 |
| Hematocrit - low | 5 |
| Hemoglobin - low | 6 |
| Platelets - high | 1 |
| Platelets - low | 9 |
| RBC - low | 12 |
| WBC - high | 1 |
| WBC - low | 7 |
| Neutrophils - high | 1 |
| Neutrophils - low | 3 |
| PT (INR) - high | 2 |
| ASAT (SGOT) - high | 6 |
| LDH - high | 2 |
| ALAT (SGPT) - high | 7 |
| Alk. Phos. - high | 6 |
| Dir. Bilirubin - high | 3 |
| Total Bilirubin - high | 2 |
| Creatinine - high | 0 |
| Albumin - low | 4 |
| Potassium - low | 2 |
| Sodium - low | 2 |
| Calcium - low | 1 |
| Glucose Fasting - high | 4 |
Collected over Approximately 3 Years (up to 28 days after the last intake of study medication). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Capecitabine+ Oxaliplatin+ Bevacizumab | — | 16/36 (44.4%) | 36/36 (100%) |
| Event | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| DehydrationMetabolism and nutrition disorders | 6/36 |
| DiarrhoeaGastrointestinal disorders | 4/36 |
| PyrexiaGeneral disorders | 3/36 |
| Abdominal painGastrointestinal disorders | 2/36 |
| Gastrointestinal haemorrhageGastrointestinal disorders | 2/36 |
| NeutropeniaBlood and lymphatic system disorders | 2/36 |
| EnteritisGastrointestinal disorders | 1/36 |
| Intestinal obstructionGastrointestinal disorders | 1/36 |
| VomitingGastrointestinal disorders | 1/36 |
| PainGeneral disorders | 1/36 |
| Event | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| FatigueGeneral disorders | 32/36 |
| NauseaGastrointestinal disorders | 30/36 |
| DiarrhoeaGastrointestinal disorders | 29/36 |
| Peripheral sensory neuropathyNervous system disorders | 22/36 |
| VomitingGastrointestinal disorders | 21/36 |
| Palmar-plantarSkin and subcutaneous tissue disorders | 20/36 |
| AnorexiaMetabolism and nutrition disorders | 20/36 |
| Abdominal painGastrointestinal disorders | 14/36 |
| Neuropathy peripheralNervous system disorders | 14/36 |
| NeutropeniaBlood and lymphatic system disorders | 11/36 |
| Age, Continuous(Years) | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| Mean | 57.3 ± 13.03 |
| Sex: Female, Male(Participants) | Capecitabine+ Oxaliplatin+ Bevacizumab |
|---|---|
| Female | 21 |
| Male | 15 |
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