ELVN-002 With Trastuzumab +/- Chemotherapy in HER2+ Solid Tumors, Colorectal and Breast Cancer

Enliven Therapeutics

Status and phase

Active, not recruiting

Phase 1

Conditions

HER2 Positive Solid Tumors

HER2-positive Gastric Cancer

HER2 Amplification

HER2-positive Breast Cancer

Colorectal Cancer

Treatments

Drug: Leucovorin

Drug: ELVN-002

Drug: paclitaxel

Drug: Capecitabine

Drug: Trastuzumab

Drug: Oxaliplatin

Drug: 5-Fluorouracil

Drug: Eribulin

Study type

Interventional

Funder types

Industry

Identifiers

NCT06328738

ELVN-002-003

Details and patient eligibility

About

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.

Full 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.

Enrollment

275 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Sequential Assignment

Masking

None (Open label)

275 participants in 13 patient groups

Part 1: ELVN-002 + trastuzumab dose escalation

Experimental group

Description:

Treatment:

Drug: Trastuzumab

Drug: ELVN-002

Part 2A: ELVN-002 + trastuzumab + CAPEOX dose escalation in colorectal cancer

Experimental group

Description:

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered IV (intravenously) in 21-day cycles, at 8mg/kg on cycle 1 day 2 followed by a dose of 6mg/kg on day 1 of cycles 2+. Capecitabine will be administered orally twice daily at 1000 mg/m2 on days 1 - 14 of a 21-day cycle. Oxaliplatin will be administered intravenously at 130 mg/m2 on day 1 of a 21-day cycle.

Treatment:

Drug: Oxaliplatin

Drug: Trastuzumab

Drug: Capecitabine

Drug: ELVN-002

Part 2B: ELVN-002 + trastuzumab + mFOLFOX6 dose escalation in colorectal cancer

Experimental group

Description:

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered intravenously at 6 mg/kg IV cycle 1, day 2 followed by 4 mg/kg IV cycle 1, day 15, and then one dose at 4mg/kg IV every 14 days. Fluorouracil (5-FU) will be administered intravenously as a 400 mg/m2 IV bolus on days 1 and 15 followed by 2400 mg/m2 over 46-48 hours of continuous infusion on days 1-3 and days 15-17 of a 28-day cycle. Leucovorin will be administered intravenously at 400 mg/m2 concurrently with oxaliplatin on days 1 and 15 of a 28-day cycle. Oxaliplatin will be administered intravenously at 85 mg/m2 IV on day 1 and 15 of a 28-day cycle.

Treatment:

Drug: Oxaliplatin

Drug: 5-Fluorouracil

Drug: Trastuzumab

Drug: ELVN-002

Drug: Leucovorin

Part 2C: ELVN-002 + trastuzumab + capecitabine dose escalation in breast cancer

Experimental group

Description:

Treatment:

Drug: Trastuzumab

Drug: Capecitabine

Drug: ELVN-002

Part 2D: ELVN-002 + trastuzumab + paclitaxel dose escalation in solid tumors

Experimental group

Description:

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered IV (intravenously) in 21-day cycles, at 8mg/kg on cycle 1 day 2 followed by a dose of 6mg/kg on day 1 of cycles 2+. Paclitaxel will be administered intravenously at 80 mg/m2 on days 1, 8, and 15 of a 21-day cycle.

Treatment:

Drug: Trastuzumab

Drug: paclitaxel

Drug: ELVN-002

Part 2E: ELVN-002 + trastuzumab + eribulin dose escalation in breast cancer

Experimental group

Description:

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered IV (intravenously) in 21-day cycles, at 8mg/kg on cycle 1 day 2 followed by a dose of 6mg/kg on day 1 of cycles 2+. Eribulin will be administered intravenously at 1.4 mg/m2 on days 1 and 8 of a 21-day cycle.

Treatment:

Drug: Eribulin

Drug: Trastuzumab

Drug: ELVN-002

Part 3A: ELVN-002 + trastuzumab dose expansion in colorectal cancer

Experimental group

Description:

Treatment:

Drug: Trastuzumab

Drug: ELVN-002

Part 3B: ELVN-002 + trastuzumab dose expansion in breast cancer

Experimental group

Description:

Treatment:

Drug: Trastuzumab

Drug: ELVN-002

Part 3C: ELVN-002 + trastuzumab dose expansion in other solid tumor type 1

Experimental group

Description:

Treatment:

Drug: Trastuzumab

Drug: ELVN-002

Part 3D: ELVN-002 + trastuzumab dose expansion in other solid tumor type 2

Experimental group

Description:

Treatment:

Drug: Trastuzumab

Drug: ELVN-002

Part 3E: ELVN-002 + trastuzumab dose expansion in other solid tumor type 3

Experimental group

Description:

Treatment:

Drug: Trastuzumab

Drug: ELVN-002

Part 4A: ELVN-002 + trastuzumab + CAPEOX dose expansion in colorectal cancer

Experimental group

Description:

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered IV (intravenously) in 21-day cycles, at 8mg/kg on cycle 1 day 2 followed by a dose of 6mg/kg on day 1 of cycles 2+. Capecitabine will be administered orally twice daily at 1000 mg/m2 on Days 1 - 14 of a 21-day cycle. Oxaliplatin: will be administered intravenously at 130 mg/m2 on Day 1 of a 21-day cycle.

Treatment:

Drug: Oxaliplatin

Drug: Trastuzumab

Drug: Capecitabine

Drug: ELVN-002

Part 4B: ELVN-002 + trastuzumab + mFOLFOX6 dose expansion in colorectal cancer

Experimental group

Description:

Treatment:

Drug: Oxaliplatin

Drug: 5-Fluorouracil

Drug: Trastuzumab