Advanced Colorectal Carcinoma
Conditions
Brief summary
A Phase 1 dose escalation study to evaluate APR003 in patients with advanced colorectal cancer (CRC) with malignant liver lesions
Detailed description
APR003 is a small molecule TLR7 agonist that concentrates in the GI, and liver with limited systemic exposure. It is designed to increase the therapeutic window of a TLR7 agonist by minimizing the side-effects associated with generalized systemic immune activation and inflammation.
Interventions
DRUGAPR003
This portion of the study further explores the clinical activity, safety, pharmacokinetics and pharmacology of APR003 monotherapy at the RP2D and to assess the antitumor activity of APR003 in subjects with unresectable CRC with liver metastases.
Sponsors
Apros Therapeutics, Inc
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1 Dose Escalation
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* ECOG performance status of 0 or 1 * Must have disease that is considered non-surgically resectable. * Relapsed or persistent/refractory to at least two prior systemic treatment regimens for locally advanced or metastatic disease considered to be standard-of-care (SOC). * Must have previously received an irinotecan or oxaliplatin-based therapy, as well as a targeted antibody therapy for metastatic disease * Tumors that are MSI-H/dMMR must have previously received checkpoint inhibitor therapy * Adequate hepatic function * Adequate renal function * Normal coagulation panel * Willingness to use effective contraception
Exclusion criteria
* Current or history of CNS metastases * Significant cardiovascular disease * Pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Total Plasma Clearance (CL/F) of APR003 | Cycle 1 Day 1 (Cycle duration is 21 days) | Plasma concentration of APR003 was analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Standard PK parameters were determined using non-compartmental methods. |
| Determine the Number of Patients With Dose Limiting Toxicities (DLTs) | Until disease progression, or up to approximately 15 months and 18 days, whichever is first | Determine the number of patients who have experienced a Dose Limiting Toxicities (DLT) evaluated by the investigator based on CTCAE Severity Grade. |
| Maximum Concentration (Cmax) of APR003 | Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (Cycle duration is 21 days) | Plasma concentration of APR003 was analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Standard PK parameters were determined using non-compartmental methods. |
| Time-to-maximum Concentration (Tmax) of APR003 | Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (Cycle duration is 21 days) | Plasma concentration of APR003 was analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Standard PK parameters were determined using non-compartmental methods. |
| Area Under the Curve (AUC) From Time Zero to 24 hr (AUC0-24) of APR003 | Cycle 1 Day 1, Cycle 1 Day 15 (Cycle duration is 21 days) | Plasma concentration of APR003 was analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Standard PK parameters were determined using non-compartmental methods. |
| AUC From Time Zero to Time Infinity (AUC0-ꝏ) of APR003 | Cycle 1 Day 1 (Cycle duration is 21 days) | Plasma concentration of APR003 was analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Standard PK parameters were determined using non-compartmental methods. |
| AUC Over the Dosing Interval (AUClast) of APR003 | Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (Cycle duration is 21 days) | Plasma concentration of APR003 was analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Standard PK parameters were determined using non-compartmental methods. |
| Elimination Half-life (T1/2) of APR003 | Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (Cycle duration is 21 days) | Plasma concentration of APR003 was analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Standard PK parameters were determined using non-compartmental methods. |
| Apparent Volume of Distribution at Steady State After Administration (Vss/F) of APR003 | Cycle 1 Day 1 (Cycle duration is 21 days) | Plasma concentration of APR003 was analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Standard PK parameters were determined using non-compartmental methods. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | Until disease progression, or up to approximately 15 months and 18 days, whichever is first | Objective response rate (ORR), defined as the proportion of patients with either a complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort -1 25 MG once a week | 6 |
| Cohort 1 50 MG once a week | 4 |
| Cohort 2 100 MG once a week | 1 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 3 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Disease Progression | 3 | 3 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 | Total | Cohort -1 | Cohort 2 |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 10 Participants | 5 Participants | 1 Participants |
| Age, Continuous | 52 years | 52 years | 50.5 years | 52 years |
| Colorectal Type Adenocarcinoma | 4 Participants | 10 Participants | 5 Participants | 1 Participants |
| Colorectal Type Mucinous | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Current Stage-Metastasis (M) M1 | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Current Stage-Metastasis (M) M1b | 4 Participants | 9 Participants | 4 Participants | 1 Participants |
| Current Stage-Tumor (T) T2 | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Current Stage-Tumor (T) T3 | 1 Participants | 6 Participants | 5 Participants | 0 Participants |
| Current Stage-Tumor (T) T4 | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Current Stage-Tumor (T) T4a | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Current Stage-Tumor (T) Unknown | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| ECOG Performance Status | 0.5 units on a scale | 1 units on a scale | 1 units on a scale | 0 units on a scale |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 10 Participants | 6 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Grade at Study Entry G1 | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Grade at Study Entry G2 | 1 Participants | 7 Participants | 5 Participants | 1 Participants |
| Grade at Study Entry GX (grade not assessed) | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Grade at Study Entry Unknown | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Primary Tumor Location Colon, Left | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| Primary Tumor Location Colon, Right | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Primary Tumor Location Other | 1 Participants | 5 Participants | 4 Participants | 0 Participants |
| Primary Tumor Location Rectal | 1 Participants | 3 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 9 Participants | 5 Participants | 0 Participants |
| Region of Enrollment United States | 4 participants | 11 participants | 6 participants | 1 participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 4 Participants | 8 Participants | 4 Participants | 0 Participants |
| Stage at Trial Entry IV | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Stage at Trial Entry IVB | 4 Participants | 7 Participants | 2 Participants | 1 Participants |
| Stage at Trial Entry IVC | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 6 | 1 / 4 | 0 / 1 |
| other Total, other adverse events | 6 / 6 | 3 / 4 | 1 / 1 |
| serious Total, serious adverse events | 2 / 6 | 0 / 4 | 1 / 1 |
Outcome results
Primary
Apparent Total Plasma Clearance (CL/F) of APR003
Plasma concentration of APR003 was analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Standard PK parameters were determined using non-compartmental methods.
Time frame: Cycle 1 Day 1 (Cycle duration is 21 days)
Population: One patient in Cohort 1 was dose-reduced after the first dose from 50 MG to 25 MG and was included only in the Cycle 1 Day 1 analysis. The only patient in Cohort 2 was not analyzed due to incomplete blood collection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort -1 | Apparent Total Plasma Clearance (CL/F) of APR003 | 46.0 L/hr | Standard Deviation 15.7 |
| Cohort 1 | Apparent Total Plasma Clearance (CL/F) of APR003 | 105 L/hr | Standard Deviation 23.1 |
Primary
Apparent Volume of Distribution at Steady State After Administration (Vss/F) of APR003
Plasma concentration of APR003 was analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Standard PK parameters were determined using non-compartmental methods.
Time frame: Cycle 1 Day 1 (Cycle duration is 21 days)
Population: One patient in Cohort 1 was dose-reduced after the first dose from 50 MG to 25 MG and was included only in the Cycle 1 Day 1 analysis. The only patient in Cohort 2 was not analyzed due to incomplete blood collection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort -1 | Apparent Volume of Distribution at Steady State After Administration (Vss/F) of APR003 | 265 L | Standard Deviation 102 |
| Cohort 1 | Apparent Volume of Distribution at Steady State After Administration (Vss/F) of APR003 | 711 L | Standard Deviation 314 |
Primary
Area Under the Curve (AUC) From Time Zero to 24 hr (AUC0-24) of APR003
Plasma concentration of APR003 was analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Standard PK parameters were determined using non-compartmental methods.
Time frame: Cycle 1 Day 1, Cycle 1 Day 15 (Cycle duration is 21 days)
Population: One patient in Cohort 1 was dose-reduced after the first dose from 50 MG to 25 MG and was included only in the Cycle 1 Day 1 analysis. The only patient in Cohort 2 was not analyzed due to incomplete blood collection.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort -1 | Area Under the Curve (AUC) From Time Zero to 24 hr (AUC0-24) of APR003 | Cycle 1 Day 1 | 597 ng*hr/mL | Standard Deviation 209 |
| Cohort -1 | Area Under the Curve (AUC) From Time Zero to 24 hr (AUC0-24) of APR003 | Cycle 1 Day 15 | 862 ng*hr/mL | Standard Deviation 355 |
| Cohort 1 | Area Under the Curve (AUC) From Time Zero to 24 hr (AUC0-24) of APR003 | Cycle 1 Day 1 | 489 ng*hr/mL | Standard Deviation 137 |
| Cohort 1 | Area Under the Curve (AUC) From Time Zero to 24 hr (AUC0-24) of APR003 | Cycle 1 Day 15 | 412 ng*hr/mL | Standard Deviation 89 |
Primary
AUC From Time Zero to Time Infinity (AUC0-ꝏ) of APR003
Plasma concentration of APR003 was analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Standard PK parameters were determined using non-compartmental methods.
Time frame: Cycle 1 Day 1 (Cycle duration is 21 days)
Population: One patient in Cohort 1 was dose-reduced after the first dose from 50 MG to 25 MG and was included only in the Cycle 1 Day 1 analysis. The only patient in Cohort 2 was not analyzed due to incomplete blood collection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort -1 | AUC From Time Zero to Time Infinity (AUC0-ꝏ) of APR003 | 601 ng*hr/mL | Standard Deviation 212 |
| Cohort 1 | AUC From Time Zero to Time Infinity (AUC0-ꝏ) of APR003 | 497 ng*hr/mL | Standard Deviation 134 |
Primary
AUC Over the Dosing Interval (AUClast) of APR003
Plasma concentration of APR003 was analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Standard PK parameters were determined using non-compartmental methods.
Time frame: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (Cycle duration is 21 days)
Population: One patient in Cohort 1 was dose-reduced after the first dose from 50 MG to 25 MG and was included only in the Cycle 1 Day 1 analysis. The only patient in Cohort 2 was not analyzed due to incomplete blood collection.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort -1 | AUC Over the Dosing Interval (AUClast) of APR003 | Cycle 1 Day 1 | 597 ng*hr/mL | Standard Deviation 209 |
| Cohort -1 | AUC Over the Dosing Interval (AUClast) of APR003 | Cycle 1 Day 15 | 830 ng*hr/mL | Standard Deviation 330 |
| Cohort -1 | AUC Over the Dosing Interval (AUClast) of APR003 | Cycle 2 Day 1 | 525 ng*hr/mL | Standard Deviation 370 |
| Cohort 1 | AUC Over the Dosing Interval (AUClast) of APR003 | Cycle 1 Day 1 | 489 ng*hr/mL | Standard Deviation 137 |
| Cohort 1 | AUC Over the Dosing Interval (AUClast) of APR003 | Cycle 1 Day 15 | 443 ng*hr/mL | Standard Deviation 112 |
| Cohort 1 | AUC Over the Dosing Interval (AUClast) of APR003 | Cycle 2 Day 1 | 335 ng*hr/mL | Standard Deviation 147 |
Primary
Determine the Number of Patients With Dose Limiting Toxicities (DLTs)
Determine the number of patients who have experienced a Dose Limiting Toxicities (DLT) evaluated by the investigator based on CTCAE Severity Grade.
Time frame: Until disease progression, or up to approximately 15 months and 18 days, whichever is first
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort -1 | Determine the Number of Patients With Dose Limiting Toxicities (DLTs) | 0 participants |
| Cohort 1 | Determine the Number of Patients With Dose Limiting Toxicities (DLTs) | 0 participants |
| Cohort 2 | Determine the Number of Patients With Dose Limiting Toxicities (DLTs) | 1 participants |
Primary
Elimination Half-life (T1/2) of APR003
Plasma concentration of APR003 was analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Standard PK parameters were determined using non-compartmental methods.
Time frame: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (Cycle duration is 21 days)
Population: One patient in Cohort 1 was dose-reduced after the first dose from 50 MG to 25 MG and was included only in the Cycle 1 Day 1 analysis. The only patient in Cohort 2 was not analyzed due to incomplete blood collection.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort -1 | Elimination Half-life (T1/2) of APR003 | Cycle 1 Day 1 | 4.03 hr | Standard Deviation 0.816 |
| Cohort -1 | Elimination Half-life (T1/2) of APR003 | Cycle 1 Day 15 | 1.78 hr | Standard Deviation 0.63 |
| Cohort -1 | Elimination Half-life (T1/2) of APR003 | Cycle 2 Day 1 | 1.56 hr | Standard Deviation 0.485 |
| Cohort 1 | Elimination Half-life (T1/2) of APR003 | Cycle 1 Day 1 | 4.56 hr | Standard Deviation 1.29 |
| Cohort 1 | Elimination Half-life (T1/2) of APR003 | Cycle 1 Day 15 | 1.77 hr | Standard Deviation 0.279 |
Primary
Maximum Concentration (Cmax) of APR003
Plasma concentration of APR003 was analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Standard PK parameters were determined using non-compartmental methods.
Time frame: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (Cycle duration is 21 days)
Population: One patient in Cohort 1 was dose-reduced after the first dose from 50 MG to 25 MG and was included only in the Cycle 1 Day 1 analysis. The only patient in Cohort 2 was not analyzed due to incomplete blood collection.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort -1 | Maximum Concentration (Cmax) of APR003 | Cycle 1 Day 1 | 224 ng/mL | Standard Deviation 124 |
| Cohort -1 | Maximum Concentration (Cmax) of APR003 | Cycle 1 Day 15 | 362 ng/mL | Standard Deviation 150 |
| Cohort -1 | Maximum Concentration (Cmax) of APR003 | Cycle 2 Day 1 | 217 ng/mL | Standard Deviation 157 |
| Cohort 1 | Maximum Concentration (Cmax) of APR003 | Cycle 1 Day 1 | 158 ng/mL | Standard Deviation 85.4 |
| Cohort 1 | Maximum Concentration (Cmax) of APR003 | Cycle 1 Day 15 | 148 ng/mL | Standard Deviation 85.4 |
| Cohort 1 | Maximum Concentration (Cmax) of APR003 | Cycle 2 Day 1 | 121 ng/mL | Standard Deviation 65.3 |
Primary
Time-to-maximum Concentration (Tmax) of APR003
Plasma concentration of APR003 was analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Standard PK parameters were determined using non-compartmental methods.
Time frame: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (Cycle duration is 21 days)
Population: One patient in Cohort 1 was dose-reduced after the first dose from 50 MG to 25 MG and was included only in the Cycle 1 Day 1 analysis. The only patient in Cohort 2 was not analyzed due to incomplete blood collection.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cohort -1 | Time-to-maximum Concentration (Tmax) of APR003 | Cycle 1 Day 1 | 0.750 hr |
| Cohort -1 | Time-to-maximum Concentration (Tmax) of APR003 | Cycle 1 Day 15 | 1.00 hr |
| Cohort -1 | Time-to-maximum Concentration (Tmax) of APR003 | Cycle 2 Day 1 | 1 hr |
| Cohort 1 | Time-to-maximum Concentration (Tmax) of APR003 | Cycle 1 Day 1 | 2.00 hr |
| Cohort 1 | Time-to-maximum Concentration (Tmax) of APR003 | Cycle 1 Day 15 | 2.00 hr |
| Cohort 1 | Time-to-maximum Concentration (Tmax) of APR003 | Cycle 2 Day 1 | 2.00 hr |
Secondary
Objective Response Rate
Objective response rate (ORR), defined as the proportion of patients with either a complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1
Time frame: Until disease progression, or up to approximately 15 months and 18 days, whichever is first
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort -1 | Objective Response Rate | 0 Participants |
| Cohort 1 | Objective Response Rate | 0 Participants |
| Cohort 2 | Objective Response Rate | 0 Participants |