Safety/Efficacy Study of Imprime PGG With Cetuximab in Patients With Recurrent/Progressive Colorectal Carcinoma

A Phase 1b, Safety, PK, and Efficacy, Multicenter, Dose-Escalating Study of Imprime PGG in Combination With Cetuximab With and Without Irinotecan Therapy in Patients With Recurrent/Progressive Colorectal Carcinoma Following Treatment With a 5-FU Regimen.

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00545545

Enrollment

Registered

2007-10-17

Start date

2007-10-31

Completion date

2009-12-31

Last updated

2025-03-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Progressive Colorectal Carcinoma, Recurrent Colorectal Carcinoma

Keywords

Colorectal, Carcinoma, Recurrent, Progressive, Cetuximab, Irinotecan, 5-Fluorouracil

Brief summary

Phase 1b, safety, pharmacokinetic, and efficacy, multicenter, dose-escalating Study of Imprime PGG™ Injection dosed in combination with Cetuximab and concomitant irinotecan therapy. Enrolled patients will have a confirmed diagnosis of recurrent or progressive colorectal carcinoma following treatment with a 5-fluorouracil-containing regimen.

Interventions

BIOLOGICALImprime PGG 2 mg/kg

Infusion of 2mg/kg on Day 1 of each week for 6 weeks (one cycle) Number of Cycles: until progression or unacceptable toxicity develops.

BIOLOGICALImprime PGG 4 mg/kg

Infusion of 4mg/kg on Day 1 of each week for 6 weeks (one cycle). Number of Cycles: until progression or unacceptable toxicity develops.

BIOLOGICALCetuximab

Infusion 400 mg/m2 over 2 hours on Day 1, then 250 mg/m2 over 1 hour on Days 8, 15, 22, 29, and 36 of each 6-week treatment cycle;

DRUGIrinotecan

Infusion 125 mg/m2 i.v. over 1.5 hours on Days 1, 8, 15, and 22 of each 6-week treatment cycle

BIOLOGICALImprime PGG 6mg/kg

Infusion of 6mg/kg on Day 1 of each week for 6 weeks (one cycle) Number of Cycles: until progression or unacceptable toxicity develops.

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

Inclusion criteria

1. Is between the ages of 18 and 75 years old, inclusive; 2. Has a recurrent or progressive carcinoma of the colon or rectum with documented histological confirmation of primary carcinoma; 3. Has measurable disease, defined as at least one tumor that fulfills the criteria for a target lesion according to RECIST; 4. Has previously received treatment with 5-FU, alone or in combination with other anti-tumor medications (except as in exclusion #1 below); Prior treatment with capecitabine (Xeloda®) will be considered to fulfill the requirement for prior treatment with 5-FU; 5. Has a Karnofsky Score of ≥ 70; 6. Has a life expectancy of \> 3 months; 7. Has adequate bone marrow reserve as evidenced by: 1. ANC ≥ 1,500/μL 2. PLT ≥ 100,000/μL 3. HGB ≥ 9 g/dl; 8. Has adequate renal function as evidenced by serum creatinine ≤ 1.5X the upper limit of normal (ULN) for the reference lab; 9. Has adequate hepatic function as evidenced by: 1. Serum total bilirubin ≤ 1.0 mg/dL 2. AST ≤ 3X ULN for the reference lab (≤ 5X ULN for patients with known hepatic metastases) 3. ALT ≤ 3X ULN for the reference lab (≤ 5X ULN for patients with known hepatic metastases); 10. Has discontinued any CYP3A4 enzyme-inducing anticonvulsants (such as phenytoin, phenobarbital or carbamazepine) and antimicrobials (such as refampin and rifabutin), St. John's Wort, and ketoconasole at least two weeks prior to Day 1 11. Has recovered from the effects of any prior surgery, radiotherapy, or chemotherapy; 12. Has read, understood and signed the informed consent form (ICF) approved by the Independent Review Board/Ethics Committee (IRB/EC); and 13. If a woman of childbearing potential or a fertile man (and his partners), must agree to use an effective form of contraception during the study and for 120 days following the last dose of study medication (an effective form of contraception is an hormonal contraceptive or a double-barrier method).

Exclusion criteria

1. Has previously received treatment with cetuximab or irinotecan; 2. Has a known hypersensitivity to cetuximab, murine proteins, or any component of cetuximab; 3. Has a hereditary fructose intolerance; 4. Has a known hypersensitivity to baker's yeast, or has an active yeast infection; 5. Has had previous exposure to Betafectin® or Imprime PGG; 6. Has received previous radiation therapy to \>30% of active bone marrow; 7. Has a fever of \>38.5º C within 3 days prior to initial dosing; 8. Has known or suspected central nervous system (CNS) metastases; 9. Had a second malignancy within the previous 5 years, except for basal cell carcinoma, cervical intra-epithelial neoplasia or curatively-treated prostate cancer with a PSA of \< 2.0 ng/mL; 10. Has known HIV/AIDS, Hepatitis B, Hepatitis C, connective tissue or autoimmune disease, or other clinical diagnosis, ongoing or intercurrent illness that in the investigator's opinion would prevent participation; 11. If female, is pregnant or breast-feeding; 12. Is receiving concurrent investigational therapy or has received investigational therapy within a period of 30 days prior to the first scheduled day of dosing (investigational therapy is defined as treatment for which there is currently no regulatory-authority-approved indication); or 13. Has previously received an organ or progenitor/stem cell transplant.

Design outcomes

Primary

Measure	Time frame	Description
Safety and Maximum Tolerated Dosage of Imprime PGG When Used in Combination With Cetuximab With or Without Irinotecan Therapy	From the date of the first dose of study drug to disease progression or until development of a drug toxicity that precludes further protocol treatment, up to 15 months	Safety and maximum tolerated dosage (MTD) of Imprime PGG was determined by the Adverse Events Task Force based on the drug-related adverse events experienced by subjects that met the criteria for a dose limiting toxicity (DLT) within a timeframe of the first 3 weeks of treatment and 1 week follow-up. If one in the initial three subjects for a dose group experienced a DLT, three additional subjects were enrolled in that dose group. If two or more subjects in the expanded dose group experienced a DLT, the study was to be stopped and the MTD was defined as the dose prior to the dose at which the DLT was observed. If a DLT occurred in the first dose group (2 mg/kg Imprime PGG), the protocol allowed for the next group to be dosed at a reduced dose of 1 mg/kg Imprime PGG. The dose groups described above were: Dose Group 1 (Imprime PGG 2 mg/kg), Dose Group 2 (Imprime PGG 4 mg/kg), Dose Group 3 (Imprime PGG 6 mg/kg).

Secondary

Measure	Time frame	Description
Overall Response Rate (ORR) Per RECIST Criteria v1.0 in Each Study Arm	From the date of the first dose of study drug to disease progression or last objective evaluation of the tumor before treatment discontinuation due to any reason, up to 15 months	The overall response rate was defined as the number of participants experiencing a best tumor response of either complete response (CR; disappearance of all target lesions) or partial response (PR; \>=30% decrease in the sum of diameters of target lesions) based on RECIST criteria v.1.0. Overall response rate (ORR) = CR + PR.
Disease Control Rate (DCR) Per RECIST Criteria v1.0 in Each Study Arm	From the date of the first dose of study drug to disease progression or last objective evaluation of the tumor before treatment discontinuation due to any reason, up to 15 months	The disease control rate was defined as the number of participants experiencing a best tumor response of either complete response (CR; disappearance of all target lesions), partial response (PR; \>=30% decrease in the sum of diameters of target lesions) or stable disease (SD) based on RECIST criteria v.1.0. Disease control rate (DCR) = CR + PR + SD.
Rate of Number of Participants With Tumor Response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) in Each Study Arm	From the date of the first dose of study drug to disease progression or last objective evaluation of the tumor before treatment discontinuation due to any reason, up to 15 months	The best observed overall response rates were defined as the number of participants experiencing a best tumor response of either complete response (CR; disappearance of all target lesions), partial response (PR; \>=30% decrease in the sum of diameters of target lesions), stable disease (SD) or progressive disease (PD) based on RECIST criteria v1.0.
Duration of Overall Tumor Response in Each Study Arm	The time from the date of the first dose of study drug to the date of the first documented progression or last objective evaluation of the tumor before treatment discontinuation due to any reason, up to 15 months	The duration of objective tumor response was defined as the time from the date of the first documented CT scan showing CR (disappearance of all target lesions) or PR (\>=30% decrease in the sum of diameters of target lesions), whichever occurred first, to the date of the first documented progression (date of CT scan where PD was first observed; or where progression was first observed if based on a clinical assessment).
Duration of Disease Control in Each Study Arm	The time from the date of first dose of study drug to the date of first documented progression, or last objective evaluation of the tumor before treatment discontinuation due to any reason, up to 15 months	Duration of stable disease (SD) was to be an efficacy variable, however, duration of disease control was used in place of duration of stable disease, as it is a more clinically meaning measure of the effectiveness of the treatment. Duration of disease control was defined as the time from the date of the first documented CT scan showing CR (disappearance of all target lesions), PR (\>=30% decrease in the sum of diameters of target lesions) or SD, whichever occurred first, to the date of the first documented progression (date of CT scan where PD was first observed; or where progression was first observed if based on a clinical assessment).
Duration of Time-to-Progression (TTP) in Each Study Arm	The time from the date of the first dose of study drug to the date of the first documented progression or last objective evaluation of the tumor before treatment discontinuation due to any reason, up to 15 months	Time-to-progression (TTP) was defined as the time from the date of the first dose of study drug to the date of the first documented progression (date of the CT scan where progression was first observed; or where progression was first observed if clinical assessment). Subjects who did not progress were censored at the last objective evaluation (the date of the last CT scan; or last observed clinical assessment).

Countries

Philippines

Participant flow

Recruitment details

A phase 1b/2 dose-escalating (ascending dose model) design with 10 subjects enrolled in stage 1, 22 additional subjects in stage 2, for a total of 32 subjects enrolled sequentially into two treatment arms across Southeast Asia clinical sites. First subject enrolled: 15 Oct 2007 Last subject last visit: 04 Nov 2009

Pre-assignment details

A total of 32 participants enrolled, all participants received at least one dose of study treatment.

Participants by arm

Arm	Count
Arm 1, Imprime PGG Injection 2 mg/kg+ Cetuximab + Irinotecan Imprime PGG® infusion: 2 mg/kg i.v. over 1 hr on Days 1, 8, 15, 22, 29, and 36 of each 6-week treatment cycle; Cetuximab infusion: 400 mg/m2 over 2 hours on Day 1, then 250 mg/m2 over 1 hour on Days 8, 15, 22, 29, and 36 of each 6-week treatment cycle; Irinotecan infusion: 125 mg/m2 i.v. over 1.5 hours on Days 1, 8, 15, and 22 of each 6-week treatment cycle	3
Arm 1, Imprime PGG Injection 4 mg/kg+ Cetuximab + Irinotecan Imprime PGG® infusion: 4 mg/kg i.v. over 2 hours on Days 1, 8, 15, 22, 29, and 36 of each 6-week treatment cycle; Cetuximab infusion: 400 mg/m2 over 2 hours on Day 1, then 250 mg/m2 over 1 hour on Days 8, 15, 22, 29, and 36 of each 6-week treatment cycle; Irinotecan infusion: 125 mg/m2 i.v. over 1.5 hours on Days 1, 8, 15, and 22 of each 6-week treatment cycle	7
Arm 1, Imprime PGG Injection 6 mg/kg+ Cetuximab + Irinotecan Imprime PGG® infusion: 6 mg/kg i.v. over 3 hours on Days 1, 8, 15, 22, 29, and 36 of each 6-week treatment cycle; Cetuximab infusion: 400 mg/m2 over 2 hours on Day 1, then 250 mg/m2 over 1 hour on Days 8, 15, 22, 29, and 36 of each 6-week treatment cycle; Irinotecan infusion: 125 mg/m2 i.v. over 1.5 hours on Days 1, 8, 15, and 22 of each 6-week treatment cycle	0
Arm 2, Imprime PGG Injection 2 mg/kg+ Cetuximab Imprime PGG® infusion: 2 mg/kg i.v. over 1 hr on Days 1, 8, 15, 22, 29, and 36 of each 6-week treatment cycle; Cetuximab infusion: 400 mg/m2 over 2 hours on Day 1, then 250 mg/m2 over 1 hour on Days 8, 15, 22, 29, and 36 of each 6-week treatment cycle	4
Arm 2, Imprime PGG Injection 4 mg/kg+ Cetuximab Imprime PGG® infusion: 4 mg/kg i.v. over 2 hours on Days 1, 8, 15, 22, 29, and 36 of each 6-week treatment cycle; Cetuximab infusion: 400 mg/m2 over 2 hours on Day 1, then 250 mg/m2 over 1 hour on Days 8, 15, 22, 29, and 36 of each 6-week treatment cycle	9
Arm 2, Imprime PGG Injection 6 mg/kg+ Cetuximab Imprime PGG® infusion: 6 mg/kg i.v. over 3 hours on Days 1, 8, 15, 22, 29, and 36 of each 6-week treatment cycle; Cetuximab infusion: 400 mg/m2 over 2 hours on Day 1, then 250 mg/m2 over 1 hour on Days 8, 15, 22, 29, and 36 of each 6-week treatment cycle	9
Total	32

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG003	FG004	FG005
Overall Study	Irinotecan intolerance	1	1	0	0	0
Overall Study	No target lesions to track post surgery	0	0	0	1	1
Overall Study	Physician Decision	1	0	0	0	1
Overall Study	Progressive Neoplastic Disease	1	5	4	8	7
Overall Study	Withdrawal by Subject	0	1	0	0	0

Baseline characteristics

Characteristic	Arm 2, Imprime PGG Injection 4 mg/kg+ Cetuximab	Arm 2, Imprime PGG Injection 6 mg/kg+ Cetuximab	Total	Arm 1, Imprime PGG Injection 2 mg/kg+ Cetuximab + Irinotecan	Arm 1, Imprime PGG Injection 4 mg/kg+ Cetuximab + Irinotecan	Arm 2, Imprime PGG Injection 2 mg/kg+ Cetuximab	Arm 1, Imprime PGG Injection 6 mg/kg+ Cetuximab + Irinotecan
Age, Continuous	52.6 years STANDARD_DEVIATION 11.8	61.9 years STANDARD_DEVIATION 9.3	55.2 years STANDARD_DEVIATION 10.9	57.0 years STANDARD_DEVIATION 6.6	52.9 years STANDARD_DEVIATION 12.4	52.0 years STANDARD_DEVIATION 10.8	—
Baseline Body Surface Area	1.6 m^2 STANDARD_DEVIATION 0.2	1.7 m^2 STANDARD_DEVIATION 0.1	1.6 m^2 STANDARD_DEVIATION 0.3	1.8 m^2 STANDARD_DEVIATION 0.2	1.6 m^2 STANDARD_DEVIATION 0.3	1.6 m^2 STANDARD_DEVIATION 0.2	—
Baseline Height	161.8 cm STANDARD_DEVIATION 9	162.1 cm STANDARD_DEVIATION 8.5	163.2 cm STANDARD_DEVIATION 9.1	168.3 cm STANDARD_DEVIATION 4.2	162.3 cm STANDARD_DEVIATION 11.6	163.3 cm STANDARD_DEVIATION 7.5	—
Baseline Karnofsky Performance Status Score	90.0 units on a scale STANDARD_DEVIATION 7.1	93.3 units on a scale STANDARD_DEVIATION 8.7	91.4 units on a scale STANDARD_DEVIATION 8.6	86.7 units on a scale STANDARD_DEVIATION 15.3	92.9 units on a scale STANDARD_DEVIATION 7.6	92.5 units on a scale STANDARD_DEVIATION 5	—
Baseline Weight	57.6 kg STANDARD_DEVIATION 11.6	63.4 kg STANDARD_DEVIATION 8.4	60.7 kg STANDARD_DEVIATION 12.7	69.5 kg STANDARD_DEVIATION 13.1	57.0 kg STANDARD_DEVIATION 15.1	60.2 kg STANDARD_DEVIATION 11.5	—
Basis of Diagnosis Cytology	1 participants	0 participants	1 participants	0 participants	0 participants	0 participants	—
Basis of Diagnosis Histology	8 participants	9 participants	31 participants	3 participants	7 participants	4 participants	—
Initial Pathologic Diagnosis Colon Carcinoma	5 participants	8 participants	19 participants	2 participants	2 participants	2 participants	—
Initial Pathologic Diagnosis Rectum Carcinoma	4 participants	1 participants	13 participants	1 participants	5 participants	2 participants	—
Race/Ethnicity, Customized East Southeast Asian	9 participants	9 participants	32 participants	3 participants	7 participants	4 participants	—
Sex: Female, Male Female	4 Participants	2 Participants	10 Participants	0 Participants	3 Participants	1 Participants	0 Participants
Sex: Female, Male Male	5 Participants	7 Participants	22 Participants	3 Participants	4 Participants	3 Participants	0 Participants
Time Since Initial Tumor Diagnosis	776.7 days STANDARD_DEVIATION 597.1	526.6 days STANDARD_DEVIATION 335.8	666.1 days STANDARD_DEVIATION 436.1	630.7 days STANDARD_DEVIATION 560.7	686.6 days STANDARD_DEVIATION 354.7	710.5 days STANDARD_DEVIATION 507.7	—

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	3 / 3	7 / 7	0 / 0	4 / 4	9 / 9	9 / 9
serious Total, serious adverse events	3 / 3	6 / 7	0 / 0	2 / 4	4 / 9	2 / 9

Outcome results

Primary

Safety and Maximum Tolerated Dosage of Imprime PGG When Used in Combination With Cetuximab With or Without Irinotecan Therapy

Safety and maximum tolerated dosage (MTD) of Imprime PGG was determined by the Adverse Events Task Force based on the drug-related adverse events experienced by subjects that met the criteria for a dose limiting toxicity (DLT) within a timeframe of the first 3 weeks of treatment and 1 week follow-up. If one in the initial three subjects for a dose group experienced a DLT, three additional subjects were enrolled in that dose group. If two or more subjects in the expanded dose group experienced a DLT, the study was to be stopped and the MTD was defined as the dose prior to the dose at which the DLT was observed. If a DLT occurred in the first dose group (2 mg/kg Imprime PGG), the protocol allowed for the next group to be dosed at a reduced dose of 1 mg/kg Imprime PGG. The dose groups described above were: Dose Group 1 (Imprime PGG 2 mg/kg), Dose Group 2 (Imprime PGG 4 mg/kg), Dose Group 3 (Imprime PGG 6 mg/kg).

Time frame: From the date of the first dose of study drug to disease progression or until development of a drug toxicity that precludes further protocol treatment, up to 15 months

Population: The safety population comprised of all subjects who received any amount of Imprime PGG.

Arm	Measure	Group	Value (NUMBER)
Arm 1, Imprime PGG Injection 2 mg/kg+ Cetuximab + Irinotecan	Safety and Maximum Tolerated Dosage of Imprime PGG When Used in Combination With Cetuximab With or Without Irinotecan Therapy	Subjects Who Received Treatment	3 participants
Arm 1, Imprime PGG Injection 2 mg/kg+ Cetuximab + Irinotecan	Safety and Maximum Tolerated Dosage of Imprime PGG When Used in Combination With Cetuximab With or Without Irinotecan Therapy	Subjects Who Discontinued the Study	3 participants
Arm 1, Imprime PGG Injection 4 mg/kg+ Cetuximab + Irinotecan	Safety and Maximum Tolerated Dosage of Imprime PGG When Used in Combination With Cetuximab With or Without Irinotecan Therapy	Subjects Who Received Treatment	7 participants
Arm 1, Imprime PGG Injection 4 mg/kg+ Cetuximab + Irinotecan	Safety and Maximum Tolerated Dosage of Imprime PGG When Used in Combination With Cetuximab With or Without Irinotecan Therapy	Subjects Who Discontinued the Study	7 participants
Arm 2, Imprime PGG Injection 2 mg/kg+ Cetuximab	Safety and Maximum Tolerated Dosage of Imprime PGG When Used in Combination With Cetuximab With or Without Irinotecan Therapy	Subjects Who Received Treatment	4 participants
Arm 2, Imprime PGG Injection 2 mg/kg+ Cetuximab	Safety and Maximum Tolerated Dosage of Imprime PGG When Used in Combination With Cetuximab With or Without Irinotecan Therapy	Subjects Who Discontinued the Study	4 participants
Arm 2, Imprime PGG Injection 4 mg/kg+ Cetuximab	Safety and Maximum Tolerated Dosage of Imprime PGG When Used in Combination With Cetuximab With or Without Irinotecan Therapy	Subjects Who Discontinued the Study	9 participants
Arm 2, Imprime PGG Injection 4 mg/kg+ Cetuximab	Safety and Maximum Tolerated Dosage of Imprime PGG When Used in Combination With Cetuximab With or Without Irinotecan Therapy	Subjects Who Received Treatment	9 participants
Arm 2, Imprime PGG Injection 6 mg/kg+ Cetuximab	Safety and Maximum Tolerated Dosage of Imprime PGG When Used in Combination With Cetuximab With or Without Irinotecan Therapy	Subjects Who Received Treatment	9 participants
Arm 2, Imprime PGG Injection 6 mg/kg+ Cetuximab	Safety and Maximum Tolerated Dosage of Imprime PGG When Used in Combination With Cetuximab With or Without Irinotecan Therapy	Subjects Who Discontinued the Study	9 participants

Secondary

Disease Control Rate (DCR) Per RECIST Criteria v1.0 in Each Study Arm

The disease control rate was defined as the number of participants experiencing a best tumor response of either complete response (CR; disappearance of all target lesions), partial response (PR; \>=30% decrease in the sum of diameters of target lesions) or stable disease (SD) based on RECIST criteria v.1.0. Disease control rate (DCR) = CR + PR + SD.

Time frame: From the date of the first dose of study drug to disease progression or last objective evaluation of the tumor before treatment discontinuation due to any reason, up to 15 months