The purpose of this study is to determine the safety profile, maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of single agent ISB1302 in subjects with HER2-positive metastatic breast cancer who have been treated with all known therapies known to confer clinical benefit.
Terminated
Phase 1/Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| ISB 1302 250 ng/kg | Part 1: Cohort 101 - ISB 1302 250 ng/kg | |
| ISB 1302 325 ng/kg | Part 1: Cohort 201 - ISB 1302 325 ng/kg | |
| ISB 1302 325 ng/kg-D1;425 ng/kg -D8,D15,D22 | Part 1:Cohort 301- ISB 1302 325 ng/kg-D1;425 ng/kg -D8,D15,D22 | |
| ISB 1302 325 ng/kg-D1;550 ng/kg -D8,D15,D22 | Part 1:Cohort 401- ISB 1302 325 ng/kg-D1;550 ng/kg -D8,D15,D22 | |
| ISB 1302 325ng/kgD1;550 ng/kg D8;700 ng/kgD15,22 | Part1Cohort501-ISB1302 325ng/kgD1;550 ng/kg D8;700 ng/kgD15,22 | |
| ISB 1302 325ng/kg D1;550 ng/kg D8;900 ng/kg D15,22 | Part1Cohort601-ISB1302 325ng/kgD1;550 ng/kg D8;900 ng/kgD15,22 | |
| ISB 1302 escalating doses,1200 ng/kg D15,22 | Part 1 Cohort 701- ISB 1302 escalating doses,1200 ng/kg D15,22 | |
| ISB 1302 at the MTD and/or RP2D dose | Part 2 (Dose Expansion) -ISB 1302 at the MTD and/or RP2D dose |
To determine the safety profile, maximum tolerated dose (MTD) and/or recommended phase 2 dose
(RP2D) of single agent ISB 1302 in subjects with HER2-positive metastatic breast cancer who
have been treated with all known therapies known to confer clinical benefit.
| Name | Type | Description | Interventions |
|---|---|---|---|
| Part 1: Cohort 101 - ISB 1302 250 ng/kg | Experimental | Cohort 101, subjects will be administered ISB 1302 by intravenous (IV) infusion on Day 1, Day 8, Day 15, and Day 22 of each 28-day treatment cycle at dose levels. Dose on D1, D8, D15, D22 is 250 ng/kg |
|
| Part 1: Cohort 201 - ISB 1302 325 ng/kg | Experimental | Cohort 201, subjects will be administered ISB 1302 by intravenous (IV) infusion on Day 1, Day 8, Day 15, and Day 22 of each 28-day treatment cycle at dose levels. Dose on D1, D8, D15, D22 is 325 ng/kg |
|
| Part 1:Cohort 301- ISB 1302 325 ng/kg-D1;425 ng/kg -D8,D15,D22 | Experimental | Cohort 301, subjects will be administered ISB 1302 by intravenous (IV) infusion on Day 1, Day 8, Day 15, and Day 22 of each 28-day treatment cycle at escalating dose levels. Dose of GBR 1302 is 325 ng/kg on D1 and 425 ng/kg on D8, D15, D22 |
|
| Part 1:Cohort 401- ISB 1302 325 ng/kg-D1;550 ng/kg -D8,D15,D22 | Experimental | Cohort 401, subjects will be administered ISB 1302 by intravenous (IV) infusion on Day 1, Day 8, Day 15, and Day 22 of each 28-day treatment cycle at escalating dose levels. Dose of ISB 1302 is 325 ng/kg on D1 and 550 ng/kg on D8, D15, D22 |
|
| Part1Cohort501-ISB1302 325ng/kgD1;550 ng/kg D8;700 ng/kgD15,22 | Experimental | Cohort 501, subjects will be administered ISB 1302 by intravenous (IV) infusion on Day 1, Day 8, Day 15, and Day 22 of each 28-day treatment cycle at escalating dose levels. Dose of ISB 1302 is 325 ng/kg on D1 and 550 ng/kg on D8, and 700 ng/kg on D15, D22 |
|
| Part1Cohort601-ISB1302 325ng/kgD1;550 ng/kg D8;900 ng/kgD15,22 | Experimental | Cohort 601, subjects will be administered ISB 1302 by intravenous (IV) infusion on Day 1, Day 8, Day 15, and Day 22 of each 28-day treatment cycle at escalating dose levels. Dose of ISB 1302 is 325 ng/kg on D1 and 550 ng/kg on D8, and 900 ng/kg on D15, D22 |
|
| Part 1 Cohort 701- ISB 1302 escalating doses,1200 ng/kg D15,22 | Experimental | Cohort 701, subjects will be administered ISB 1302 by intravenous (IV) infusion on Day 1, Day 8, Day 15, and Day 22 of each 28-day treatment cycle at escalating dose levels. Dose of ISB 1302 is 325 ng/kg on D1 and 700 ng/kg on D8, and 1200 ng/kg on D15, D22 |
|
| Part 2 (Dose Expansion) -ISB 1302 at the MTD and/or RP2D dose | Experimental | Subjects treated with ISB 1302 at the MTD and/or RP2D dose in separate groups in the Q1W and/or the Q2W dose regimen. |
|
Inclusion Criteria:
- Females with HER2-positive [IHC 2 +, with FISH confirmation] or 3+ [IHC or FISH]
metastatic breast cancer that has progressed on last therapy. No more than 4 lines of
therapy in metastatic setting (of which no more than 2 lines should be anti-HER2
antibody-based therapy).
- Measurable disease, defined as per RECIST v1.1.
- Eastern Cooperative Oncology Group (ECOG ) performance-status score of 2 or less
- Adequate bone marrow, renal, and liver function.
- Recovered from any previous surgery and no history of major surgery within the last 28
days prior to start of study drug
- Must be willing to undergo pre-treatment and on-treatment biopsies in Part 1 and Part
2.
Exclusion Criteria:
- Any suspected or proven immunocompromised state, or infections, such as history of
positive human immunodeficiency virus (HIV), known active or chronic hepatitis B virus
(HBV) or hepatitis C virus (HCV).
- Any history or evidence of clinically significant cardiovascular disease.
- Evidence of clinically significant cardiovascular and respiratory conditions
- Previous antineoplastic treatment with immune checkpoint regulator or comparable
immunotherapy within 8 weeks of starting study drug.
- Chemotherapy, radiotherapy, molecular-targeted therapy, or biological therapies
(including HER2-directed therapies) within 4 weeks of starting study drug
- Hormone therapy within 2 weeks of starting study medications.
- Diagnosed with another malignancy that requires active therapy
- Brain metastases that require directed therapy.
- Has not recovered from any therapy related toxicities from previous treatments.
- Use of any investigational drug within 4 weeks from the start of study drug.
- Any condition that, in the opinion of the Investigator, would interfere with
evaluation of the study drug or interpretation of subject safety or study results.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | Female |
| Healthy Volunteers: | No |
| Measure: | MTD: Number of DLTs (dose limiting toxicities) during the first 28 days after the first administrations of study drug (i.e. Cycle 1) in each cohort. |
| Time Frame: | 28 days |
| Safety Issue: | |
| Description: | MTD: Number of DLTs (dose limiting toxicities) during the first 28 days after the first administrations of study drug (i.e. Cycle 1) in each cohort. |
| Measure: | Incidence, nature, and intensity of AEs according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Incidence, nature, and intensity of AEs according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. |
| Measure: | Antitumor activity of ISB 1302 administered Q1W (Part 1) |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Tumor Response per RECIST v1.1. |
| Measure: | Additional preliminary anti-tumor clinical activity of ISB 1302 administered (Part 2) |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Tumor Response per RECIST v1.1 |
| Measure: | Pharmacokinetics of ISB 1302 administered Q1W (Part 1 and Part 2) -Cmax |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | PK parameter: Cmax - maximum observed serum concentration is estimated |
| Measure: | Pharmacokinetics of ISB 1302 administered Q1W (Part 1 and Part 2)-tmax |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | PK parameter: tmax - time at which Cmax is observed |
| Measure: | Pharmacokinetics of ISB 1302 administered Q1W (Part 1 and Part 2) -AUC0-tau |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | PK parameter: AUC0-tau - Area under the serum concentration-time curve over a dosing interval is estimated. |
| Measure: | Pharmacokinetics of ISB 1302 administered Q1W (Part 1 and Part 2) - AUC0-t |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | PK parameter: AUC0-t - Area under the serum concentration-time curve over the time interval from zero to last quantifiable concentration is estimated. |
| Measure: | Immunogenicity of ISB 1302 administered Q1W (Part 1 and Part 2) |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Percent incidence of antidrug antibodies (ADA) formation assessed from baseline until end of treatment (EOT) |
| Measure: | Exploratory: Pharmacodynamic biomarkers of ISB 1302 (Part 1 and Part 2) - levels of pharmacodynamic cytokines- IL-2 |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Levels of cytokines, including IL-2 will be measured in peripheral blood as part of the pharmacodynamics and safety assessment to monitor for any signs of cytokine release syndrome. |
| Measure: | Exploratory: Pharmacodynamic biomarkers of ISB 1302 (Part 1 and Part 2) - levels of pharmacodynamic cytokines- IL-6 |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Levels of cytokines, including IL-6 will be measured in peripheral blood as part of the pharmacodynamics and safety assessment to monitor for any signs of cytokine release syndrome. |
| Measure: | Exploratory: Pharmacodynamic biomarkers of ISB 1302 (Part 1 and Part 2) - levels of pharmacodynamic cytokines- IL-10 |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Levels of cytokines, including IL-10 will be measured in peripheral blood as part of the pharmacodynamics and safety assessment to monitor for any signs of cytokine release syndrome. |
| Measure: | Exploratory: Pharmacodynamic biomarkers of ISB 1302 (Part 1 and Part 2) - levels of pharmacodynamic cytokines- IFN-γ |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Levels of cytokines, including IFN-γ will be measured in peripheral blood as part of the pharmacodynamics and safety assessment to monitor for any signs of cytokine release syndrome. |
| Measure: | Exploratory: Pharmacodynamic biomarkers of ISB 1302 (Part 1 and Part 2) - levels of pharmacodynamic cytokines- TNF-α |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Levels of cytokines, including TNF-α, will be measured in peripheral blood as part of the pharmacodynamics and safety assessment to monitor for any signs of cytokine release syndrome. |
| Measure: | Exploratory: Pharmacodynamic biomarkers of ISB 1302 (Part 1 and Part 2) -Pharmacodynamic Cellular Biomarkers -CD3 |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Cellular biomarkers to be analyzed include CD3 will be assessed by fluorescence activated cell sorting (FACS) analysis of peripheral blood leucocytes as surrogate markers for ISB 1302 activity |
| Measure: | Exploratory: Pharmacodynamic biomarkers of ISB 1302 (Part 1 and Part 2) -Pharmacodynamic Cellular Biomarkers -CD4 |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Cellular biomarkers to be analyzed include CD4 will be assessed by fluorescence activated cell sorting (FACS) analysis of peripheral blood leucocytes as surrogate markers for ISB 1302 activity |
| Measure: | Exploratory: Pharmacodynamic biomarkers of ISB 1302 (Part 1 and Part 2) -Pharmacodynamic Cellular Biomarkers -CD8 |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Cellular biomarkers to be analyzed include CD8 will be assessed by fluorescence activated cell sorting (FACS) analysis of peripheral blood leucocytes as surrogate markers for ISB 1302 activity |
| Measure: | Exploratory: Pharmacodynamic biomarkers of ISB 1302 (Part 1 and Part 2) -Pharmacodynamic Cellular Biomarkers -CD25 |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Cellular biomarkers to be analyzed include CD25 will be assessed by fluorescence activated cell sorting (FACS) analysis of peripheral blood leucocytes as surrogate markers for ISB 1302 activity |
| Measure: | Exploratory: Pharmacodynamic biomarkers of ISB 1302 (Part 1 and Part 2) -Pharmacodynamic Cellular Biomarkers -CD69 |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Cellular biomarkers to be analyzed include CD69 will be assessed by fluorescence activated cell sorting (FACS) analysis of peripheral blood leucocytes as surrogate markers for ISB 1302 activity |
| Measure: | Exploratory: Pharmacodynamic biomarkers of ISB 1302 (Part 1 and Part 2) -Pharmacodynamic Cellular Biomarkers - CD127 |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Cellular biomarkers to be analyzed include CD127 will be assessed by fluorescence activated cell sorting (FACS) analysis of peripheral blood leucocytes as surrogate markers for ISB 1302 activity |
| Measure: | Exploratory: Pharmacodynamic biomarkers of ISB 1302 (Part 1 and Part 2) -Tumor tissue biopsy -Analyses of the tumor tissue include T cells |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Descriptive statistics for pharmacodynamic biomarker assessments such as Tumor tissue biopsy - Analyses of the tumor tissue include T cells |
| Measure: | Exploratory: Pharmacodynamic biomarkers of ISB 1302 (Part 1 and Part 2) -Tumor tissue biopsy -Analyses of the tumor tissue include tumor microenvironment markers |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Descriptive statistics for pharmacodynamic biomarker assessments such as Tumor tissue biopsy - Analyses of the tumor tissue include tumor microenvironment markers |
| Measure: | Exploratory: Pharmacodynamic biomarkers of ISB 1302 (Part 1 and Part 2) -Tumor tissue biopsy -Analyses of the tumor tissue include apoptotic markers |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Descriptive statistics for pharmacodynamic biomarker assessments such as Tumor tissue biopsy - Analyses of the tumor tissue include apoptotic markers |
| Measure: | Exploratory: Pharmacodynamic biomarkers of ISB 1302 (Part 1 and Part 2) -Tumor tissue biopsy -Analyses of the tumor tissue include Tumor Mutational Burden (TMB) |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Descriptive statistics for pharmacodynamic biomarker assessments such as Tumor tissue biopsy - Analyses of the tumor tissue include Tumor Mutational Burden (TMB) |
| Measure: | Exploratory: Pharmacodynamic biomarkers of ISB 1302 (Part 1 and Part 2) -Tumor tissue biopsy -Analyses of the tumor tissue include Epigenetic evaluation of Tregs |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Descriptive statistics for pharmacodynamic biomarker assessments such as Tumor tissue biopsy - Analyses of the tumor tissue include Epigenetic evaluation of Tregs |
| Measure: | Exploratory: Pharmacodynamic biomarkers of ISB 1302 (Part 1 and Part 2) -Tumor tissue biopsy -Analyses of the tumor tissue include Epigenetic evaluation of T helper cells |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Descriptive statistics for pharmacodynamic biomarker assessments such as Tumor tissue biopsy - Analyses of the tumor tissue include Epigenetic evaluation of T helper cells |
| Measure: | Exploratory: Duration of treatment (Part 1 and Part 2) |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Tumor response per RECIST v1.1 and iRECIST |
| Measure: | Exploratory: Time to disease progression (Part 1 and Part 2) |
| Time Frame: | Treatment cycles of 28 days, treatment cycles may continue, if there is clinical benefit, until disease progression, unacceptable toxicity, withdrawal, or end of study or cycles may continue beyond disease progression, treatment cycles for up to 6 months |
| Safety Issue: | |
| Description: | Tumor Response per RECIST v1.1 and iRECIST |
| Phase: | Phase 1/Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Terminated |
| Lead Sponsor: | Ichnos Sciences SA |
May 24, 2021
