HER2-positive Breast Cancer, HER2-positive Gastric Cancer, HER2 Positive Solid Tumors, HER2 Amplification, Colorectal Cancer
Conditions
Keywords
ELVN-002, HER2 positive Colorectal Cancer, HER2 overexpression, HER2
Brief summary
The purpose of this study is to determine the safety, tolerability, and recommended dose of ELVN-002 in combination with trastuzumab in participants with advanced-stage HER2-positive tumors and in combination with trastuzumab, and chemotherapy in participants with advanced-stage HER2-positive colorectal cancer and breast cancer.
Detailed description
Parts 1 and 3 of this study are designed to evaluate preliminary safety, tolerability, and pharmacokinetics (PK) of ELVN-002 in combination with trastuzumab in participants with advanced stage HER2 positive solid tumors. In addition, Part 3 will evaluate the preliminary efficacy of ELVN-002 in combination with trastuzumab in participants with advanced-stage HER2-positive solid tumors. Part 2 of this study will evaluate the preliminary safety, tolerability, and PK of ELVN-002 in combination with trastuzumab and chemotherapy; capecitabine and oxaliplatin(CAPEOX) or 5-fluorouracil (5-FU), leucovorin (LCV) and oxaliplatin (mFOLFOX6) in participants with advanced stage HER2 positive colorectal cancer, or eribulin or capecitabine in participants with advanced-stage HER2-positive breast cancer, or paclitaxel in participants with advanced stage solid tumors. In part 4, the preliminary safety, tolerability, PK, and efficacy of ELVN-002 in combination with trastuzumab and CAPEOX or mFOLFOX6 will be evaluated in participants with HER2-positive colorectal cancer.
Interventions
DRUGELVN-002
capsule
DRUGTrastuzumab
intravenous
DRUG5-Fluorouracil
intravenous
DRUGOxaliplatin
intravenous
DRUGCapecitabine
capsule
DRUGEribulin
intravenous
DRUGpaclitaxel
intravenous
DRUGLeucovorin
intravenous
Sponsors
Enliven Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1a will be a dose escalation of ELVN-002 in combination with fixed doses of trastuzumab or trastuzumab + chemotherapy according to the Bayesian Optimal Interval Design model. Phase 1b will be a dose expansion at one or more doses of ELVN-002.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pathologically or histologically documented solid tumor. * Locally advanced or relapsed/refractory disease or unresectable metastatic disease. * HER2-positive disease based on the following local testing: * Colorectal cancer: IHC3+, IHC2+/ISH+, NGS amplification by tissue (no RAS or BRAF mutation allowed) * Breast cancer: IHC3+ or IHC2+/ISH+ by tissue * Gastric cancer: IHC3+ or IHC2+/ISH+ by tissue * Other cancers: IHC3+, IHC2+/ISH+, NGS amplification by tissue or ctDNA * Prior therapies for Part 1 (Dose Escalation ELVN-002 + trastuzumab): * Colorectal cancer: treated with prior fluoropyrimidine, oxaliplatin, irinotecan-based regimens, anti-epidermal growth factor receptor (EGFR) treatment (if clinically indicated), anti-vascular endothelial growth factor (VEGF) treatment (if clinically indicated), and an anti-programmed death ligand 1 (PD-(L)-1) treatment (if the tumor is microsatellite instability (MSI)-high/deficient mismatch repair (dMMR) * Breast cancer: treated with prior taxane, pertuzumab, trastuzumab, and fam-trastuzumab deruxtecan (T-DXd) if available and appropriate based on local standard of care and investigator's assessment * Gastric cancer: treated with trastuzumab/platinum fluorouracil containing regimen and T-DXd. * Other cancers: progressed during or after ≥ 1 prior line of systemic therapy for locally advanced unresectable or metastatic disease * Prior HER2 targeted therapy is allowed * Prior therapies for Part 2 (Phase 1a Dose Escalation ELVN-002 + trastuzumab + chemotherapy): * Colorectal cancer: candidate for CAPEOX (capecitabine and oxaliplatin) or mFOLFOX6 (5-FU, LCV and oxaliplatin), and treated, if clinically indicated, with an anti-programmed death ligand 1 (PD-(L)-1) treatment (if the tumor is microsatellite instability (MSI)-high/deficient mismatch repair (dMMR). Prior HER2 targeted therapy is allowed. * Breast cancer: candidate for capecitabine, paclitaxel or eribulin, and treated with prior taxane, pertuzumab, trastuzumab, and T-DXd, if available and appropriate, based on local standard of care and investigator's assessment. No prior HER2 targeted tyrosine kinase inhibitor therapy (antibody-drug conjugates and antibodies are allowed), no prior capecitabine (for the capecitabine cohort), no prior eribulin (for the eribulin cohort), and no taxane as immediate prior therapy (paclitaxel cohort). * Prior therapies for Part 3 (Phase 1b Dose Expansion ELVN-002 + trastuzumab): * Colorectal cancer: treated with prior fluoropyrimidine, oxaliplatin, irinotecan-based regimens, anti-epidermal growth factor receptor (EGFR) treatment (if clinically indicated), anti-vascular endothelial growth factor (VEGF) treatment (if clinically indicated), and an anti-programmed death ligand 1 (PD-(L)-1) treatment if the tumor is microsatellite instability (MSI)-high/deficient mismatch repair (dMMR). No prior HER2 targeted therapy. * Breast cancer: treated with prior taxane, pertuzumab, trastuzumab, and T-DXd if available and appropriate based on local standard of care and investigator's assessment. No prior HER2 targeted tyrosine kinase inhibitor therapy (antibody-drug conjugates and antibodies are allowed). * Gastric cancer: treated with prior trastuzumab/platinum fluorouracil containing regimen and T-DXd. No prior HER2 targeted therapy. * Other cancers: Progressed during or after ≥ 1 prior line of systemic therapy for locally advanced unresectable or metastatic disease. No prior HER2 targeted therapy. * Prior therapies for Part 4 (Phase 1b Dose Expansion ELVN-002 + trastuzumab + chemotherapy): \* Colorectal cancer: candidate for CAPEOX or mFOLFOX6 and not a candidate for first-line anti-programmed death ligand 1 (PD-(L)-1) treatment (if the tumor is microsatellite instability (MSI)-high/deficient mismatch repair (dMMR). No prior therapy for metastatic disease (1 cycle of mFOLFOX6 or 1 cycle of CAPEOX allowed). No prior HER2 targeted therapy. * At least 1 measurable lesion based on RECIST v 1.1 within 6 weeks before the first dose of ELVN-002 (Part 3 and Part 4 only; Phase 1b Dose Expansion cohorts) * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 * Adequate hematological, hepatic, renal, and cardiac function
Exclusion criteria
* Treatment with anticancer therapy within a specific time before the first dose: * Chemotherapy (including ADC) ≤ 3 weeks * Immunotherapy ≤ 4 weeks * Hormonal therapy ≤ 2 weeks * TKI ≤ 2 weeks * Any experimental therapy ≤ 3 weeks or 5 half-lives, whichever is longer * Radiotherapy-wide therapy ≤ 3 weeks * Radiotherapy limited field (including stereotactic brain) ≤ 2 weeks * Antibody ≤ 3 weeks * Any brain lesion requiring immediate local therapy * Ongoing use of corticosteroids for central nervous system (CNS) symptoms at a dose of \> 2 mg daily of dexamethasone (or equivalent) * Leptomeningeal disease * Uncontrolled seizures * Participants for any chemotherapy cohort: ongoing Grade 2 or higher neuropathy of any cause * Inability to swallow pills or any significant gastrointestinal disease that would preclude adequate oral absorption of medications. * Ongoing adverse effects from prior treatment \> CTCAE Grade 1 except for Grade 2 alopecia * Corrected QT interval (QTc) of \>470 milliseconds (ms) for females or \>450 ms for males
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose limiting toxicities (DLTs; Phase 1a only) | 21 days | DLTs will be used to support that the recommended doses for expansion are \</= maximum tolerated dose (MTD) |
| Incidence of adverse events (AEs) | 24 months | AEs will be used to support that the recommended doses for expansion are likely to be tolerable |
| Incidence of laboratory abnormalities | 24 months | Clinically significant laboratory abnormalities will be used to support that the recommended doses for expansion are likely to be tolerable |
| Incidence of electrocardiogram abnormalities | 24 months | Clinically significant electrocardiogram abnormalities will be used to support that the recommended doses for expansion are likely to be tolerable |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed objective response rate (ORR) | 24 months | For patients with measurable disease at baseline, confirmed response as assessed by investigator per RECIST v1.1 |
| PK parameter of area under the curve of ELVN-002 (Phase 1a only) | 24 months | The concentration of ELVN-002 measured in the blood over 24 hours at steady state |
| Brain metastases response (Phase 1b only) | 24 months | For patients with measurable brain metastases at baseline, the percent of patients who have a confirmed response per RECIST v1.1 |
| Duration of response (DOR; Phase 1b only) | 24 months | The time from the first response to progression or death per RECIST v1.1 |
| PK parameter of maximum concentration of ELVN-002 (Phase 1a only) | 24 months | The maximum concentration of ELVN-002 measured in the blood at any time point at steady state |
| PK parameter of minimum concentration of ELVN-002 (Phase 1a only) | 24 months | The minimum concentration of ELVN-002 measured in the blood at any time point at steady |
| PK parameter of terminal half life of ELVN-002 (Phase 1a only) | 24 months | The half life of ELVN-002 calculated from the concentration of ELVN-002 measured in blood |
Countries
Belgium, France, Italy, Netherlands, South Korea, Spain, United States
Outcome results
None listed