Solid Tumor
Conditions
Brief summary
This is a single center, Phase I dose finding study of HCW9218 for the treatment of advanced/metastatic solid tumor cancer (except pancreatic and primary brain cancers). HCW9218 is a novel bi-functional fusion protein complex administered by subcutaneous (SC) injection. It is comprised of a soluble fusion of two human TGFβRII domains, human tissue factor, and human IL-15, and a second soluble fusion of two human TGFβRII domains and a sushi domain of human IL-15Rα. HCW9218 activates IL-15R signaling on effector immune cells and the dimeric TGFβRII functions as a trap for all three human TGF-β isoforms.
Interventions
DRUGHCW9218
HCW9218 at the assigned dose level is administered as a subcutaneous injection once every 3 weeks for a minimum of 2 treatment cycles unless medically contraindicated.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed advanced/metastatic solid tumor cancer (except pancreatic and primary brain cancers), has failed at least 2 prior lines of therapy given either in the recurrent or metastatic setting and must be refractory to or intolerant of existing therapy(ies) known to provide clinical benefit for their condition. * Measurable disease per RECIST v 1.1. * Acute effects of any prior therapy must have resolved to baseline or Grade ≤1 NCI CTCAE v5 except for AEs not constituting a safety risk by enrolling Investigator judgment. * Age 18 years or older at the time of consent. * ECOG Performance Status 0 or 1. * Evidence of adequate organ function within 14 days prior to enrollment as defined in Section 4.1.6. * Adequate pulmonary function with PFTs \>50% FEV1 if symptomatic or known impairment. * Sexually active persons of child-bearing potential or with partners of childbearing potential must agree to use a highly effective form of contraception (refer to Section 4.1.10 for acceptable methods) for at least 28 days after the last dose of HCW9218. * Provides voluntary written consent prior to the performance of any research related activity.
Exclusion criteria
* Pregnant or breastfeeding. * History of clinically significant vascular disease, including any of the following within 6 months prior to start of study treatment: MI or unstable angina, percutaneous coronary intervention, bypass grafting, ventricular arrhythmia requiring medication, stroke or transient ischemic attack, symptomatic peripheral arterial disease. * Marked baseline prolongation of QT/QTc interval (e.g., demonstration of a QTc interval greater or equal to 470 milliseconds by Fridericia's correction). * Known or suspected untreated CNS metastases. * Anti-cancer treatment including surgery, radiotherapy, chemotherapy, other immunotherapy, or investigational therapy within 14 days before treatment start. * Other prior malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the subject is currently in complete remission, or any other cancer from which the subject has been disease-free for 3 years after surgical treatment. * Known hypersensitivity or history of allergic reactions attributed to compounds of similar chemical or biologic composition to the agents used in the study. * Prior therapy with TGF-β antagonist, IL-15 or analogs. * Concurrent use of St. John's wort and and/or other herbal CYP modulators within 7 days of Day 1. Must agree to not use during study treatment through the end of treatment visit to be eligible. * Known autoimmune disease requiring active treatment. Persons with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. * Active systemic infection requiring parenteral antibiotic therapy. All prior infections must have resolved following optimal therapy. * Prior organ allograft or allogeneic transplantation. * Known HIV-positive or AIDS. * Psychiatric illness/social situations that would limit compliance with study requirements. * Other illness or a medical issue that in the opinion of the Investigator would exclude the subject from participating in this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Objective of the Dose Finding Component is to Determine the Maximum Tolerated Dose (MTD) of HCW9218 | through study completion, an average of 12 months | Given that little to no toxicity is expected, the MTD will be determined using an adaptation of the continual reassessment method (CRM) (O'Quigley, 1996) starting with 1 patient cohorts. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Estimate Response Rate (Complete Response (CR), Partial Response (PR) or Stable Disease (SD) | 3 months after 1st dose | Response rate will be estimated by a simple proportion with 95% confidence limits if sufficient numbers exist |
| Estimate Progression of Overall Survival (OS) | 6 months after 1st dose | Estimated with Kaplan-Meier curves |
| Estimate Progression Free Survival (PFS) | 6 months after 1st dose | Estimated with Kaplan-Meier curves |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| HCW9218 Dose Level 1 Administer HCW9218 as monotherapy at assigned dose by SC injection once every 3 weeks. Dose Level
-1 - 0.1 mg/kg
1. \- (start) 0.25 mg/kg
2. \- 0.5 mg/kg
3. \- 0.8 mg/kg
4. \- 1.2 mg/kg
HCW9218: HCW9218 at the assigned dose level is administered as a subcutaneous injection once every 3 weeks for a minimum of 2 treatment cycles unless medically contraindicated. | 3 |
| HCW9218 Dose Level 2 Administer HCW9218 as monotherapy at assigned dose by SC injection once every 3 weeks. Dose Level
-1 - 0.1 mg/kg
1. \- (start) 0.25 mg/kg
2. \- 0.5 mg/kg
3. \- 0.8 mg/kg
4. \- 1.2 mg/kg
HCW9218: HCW9218 at the assigned dose level is administered as a subcutaneous injection once every 3 weeks for a minimum of 2 treatment cycles unless medically contraindicated. | 3 |
| HCW9218 Dose Level 3 Administer HCW9218 as monotherapy at assigned dose by SC injection once every 3 weeks. Dose Level
-1 - 0.1 mg/kg
1. \- (start) 0.25 mg/kg
2. \- 0.5 mg/kg
3. \- 0.8 mg/kg
4. \- 1.2 mg/kg
HCW9218: HCW9218 at the assigned dose level is administered as a subcutaneous injection once every 3 weeks for a minimum of 2 treatment cycles unless medically contraindicated. | 3 |
| HCW9218 Dose Level 4 Administer HCW9218 as monotherapy at assigned dose by SC injection once every 3 weeks. Dose Level
-1 - 0.1 mg/kg
1. \- (start) 0.25 mg/kg
2. \- 0.5 mg/kg
3. \- 0.8 mg/kg
4. \- 1.2 mg/kg
HCW9218: HCW9218 at the assigned dose level is administered as a subcutaneous injection once every 3 weeks for a minimum of 2 treatment cycles unless medically contraindicated. | 9 |
| Total | 18 |
Baseline characteristics
| Characteristic | HCW9218 Dose Level 1 | HCW9218 Dose Level 2 | HCW9218 Dose Level 3 | HCW9218 Dose Level 4 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 0 Participants | 3 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 3 Participants | 3 Participants | 6 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 3 Participants | 9 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 2 Participants | 3 Participants | 3 Participants | 7 Participants | 15 Participants |
| Region of Enrollment United States | 3 participants | 3 participants | 3 participants | 9 participants | 18 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 1 Participants | 6 Participants | 9 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 3 / 3 | 2 / 3 | 6 / 9 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 9 / 9 |
| serious Total, serious adverse events | 2 / 3 | 0 / 3 | 0 / 3 | 4 / 9 |
Outcome results
Primary
The Primary Objective of the Dose Finding Component is to Determine the Maximum Tolerated Dose (MTD) of HCW9218
Given that little to no toxicity is expected, the MTD will be determined using an adaptation of the continual reassessment method (CRM) (O'Quigley, 1996) starting with 1 patient cohorts.
Time frame: through study completion, an average of 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Administer HCW9218 | The Primary Objective of the Dose Finding Component is to Determine the Maximum Tolerated Dose (MTD) of HCW9218 | 1.2 mg/kg |
Secondary
Estimate Progression Free Survival (PFS)
Estimated with Kaplan-Meier curves
Time frame: 6 months after 1st dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Administer HCW9218 | Estimate Progression Free Survival (PFS) | 33 Percentage of participants |
| HCW9218 Dose Level 2 | Estimate Progression Free Survival (PFS) | 0 Percentage of participants |
| HCW9218 Dose Level 3 | Estimate Progression Free Survival (PFS) | 0 Percentage of participants |
| HCW9218 Dose Level 4 | Estimate Progression Free Survival (PFS) | 11 Percentage of participants |
Secondary
Estimate Progression Free Survival (PFS)
Estimated with Kaplan-Meier curves
Time frame: 1 year after 1st dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Administer HCW9218 | Estimate Progression Free Survival (PFS) | 33 Percentage of participants |
| HCW9218 Dose Level 2 | Estimate Progression Free Survival (PFS) | 0 Percentage of participants |
| HCW9218 Dose Level 3 | Estimate Progression Free Survival (PFS) | 0 Percentage of participants |
| HCW9218 Dose Level 4 | Estimate Progression Free Survival (PFS) | 11 Percentage of participants |
Secondary
Estimate Progression of Overall Survival (OS)
Estimated with Kaplan-Meier curves
Time frame: 1 year after 1st dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Administer HCW9218 | Estimate Progression of Overall Survival (OS) | 33 Percentage of participants |
| HCW9218 Dose Level 2 | Estimate Progression of Overall Survival (OS) | 33 Percentage of participants |
| HCW9218 Dose Level 3 | Estimate Progression of Overall Survival (OS) | 33 Percentage of participants |
| HCW9218 Dose Level 4 | Estimate Progression of Overall Survival (OS) | 67 Percentage of participants |
Secondary
Estimate Progression of Overall Survival (OS)
Estimated with Kaplan-Meier curves
Time frame: 6 months after 1st dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Administer HCW9218 | Estimate Progression of Overall Survival (OS) | 67 Percentage of participants |
| HCW9218 Dose Level 2 | Estimate Progression of Overall Survival (OS) | 67 Percentage of participants |
| HCW9218 Dose Level 3 | Estimate Progression of Overall Survival (OS) | 67 Percentage of participants |
| HCW9218 Dose Level 4 | Estimate Progression of Overall Survival (OS) | 78 Percentage of participants |
Secondary
Estimate Response Rate (Complete Response (CR), Partial Response (PR) or Stable Disease (SD)
Response rate will be estimated by a simple proportion with 95% confidence limits if sufficient numbers exist
Time frame: 12 months after 1st dose
Population: Unable to analyze participants in dose level 1 due to all cause mortality.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Administer HCW9218 | Estimate Response Rate (Complete Response (CR), Partial Response (PR) or Stable Disease (SD) | 0 Participants |
| HCW9218 Dose Level 2 | Estimate Response Rate (Complete Response (CR), Partial Response (PR) or Stable Disease (SD) | 0 Participants |
| HCW9218 Dose Level 3 | Estimate Response Rate (Complete Response (CR), Partial Response (PR) or Stable Disease (SD) | 0 Participants |
| HCW9218 Dose Level 4 | Estimate Response Rate (Complete Response (CR), Partial Response (PR) or Stable Disease (SD) | 0 Participants |
Secondary
Estimate Response Rate (Complete Response (CR), Partial Response (PR) or Stable Disease (SD)
Response rate will be estimated by a simple proportion with 95% confidence limits if sufficient numbers exist
Time frame: 6 months after 1st dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Administer HCW9218 | Estimate Response Rate (Complete Response (CR), Partial Response (PR) or Stable Disease (SD) | 0 Participants |
| HCW9218 Dose Level 2 | Estimate Response Rate (Complete Response (CR), Partial Response (PR) or Stable Disease (SD) | 0 Participants |
| HCW9218 Dose Level 3 | Estimate Response Rate (Complete Response (CR), Partial Response (PR) or Stable Disease (SD) | 0 Participants |
| HCW9218 Dose Level 4 | Estimate Response Rate (Complete Response (CR), Partial Response (PR) or Stable Disease (SD) | 0 Participants |
Secondary
Estimate Response Rate (Complete Response (CR), Partial Response (PR) or Stable Disease (SD)
Response rate will be estimated by a simple proportion with 95% confidence limits if sufficient numbers exist
Time frame: 3 months after 1st dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Administer HCW9218 | Estimate Response Rate (Complete Response (CR), Partial Response (PR) or Stable Disease (SD) | 1 Participants |
| HCW9218 Dose Level 2 | Estimate Response Rate (Complete Response (CR), Partial Response (PR) or Stable Disease (SD) | 1 Participants |
| HCW9218 Dose Level 3 | Estimate Response Rate (Complete Response (CR), Partial Response (PR) or Stable Disease (SD) | 1 Participants |
| HCW9218 Dose Level 4 | Estimate Response Rate (Complete Response (CR), Partial Response (PR) or Stable Disease (SD) | 5 Participants |