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

A Phase 1a/1b Study of ELVN-002 Combined With Trastuzumab in Advanced Stage HER2+ Solid Tumors, and ELVN-002 Combined With Trastuzumab and Chemotherapy in Advanced Stage HER2+ Colorectal Cancer and Breast Cancer

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.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; HER2-positive Breast Cancer; HER2-positive Gastric Cancer; HER2 Amplification; HER2 Positive Solid Tumors
• Intervention / Treatment: Drug: ELVN-002; Drug: Oxaliplatin; Drug: Trastuzumab; Drug: Capecitabine; Drug: 5-Fluorouracil; Drug: Leucovorin; Drug: paclitaxel; Drug: Eribulin

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, capecitabine, or paclitaxel in participants with advanced-stage HER2-positive breast cancer.

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.

• Study Type: Interventional
• Enrollment (Estimated): 255
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Helen L Collins, MD; Phone Number: 7077993272; Email: helen.collins@enliventherapeutics.com

Study Locations

• United States
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • NEXT Virginia
      • Contact: Alexander Spira, MD; Phone Number: 703-636-1473

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

13

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: ELVN-002 + trastuzumab dose escalation; 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+.	Drug: ELVN-002; capsule; Drug: Trastuzumab; intravenous
Experimental: Part 2A: ELVN-002 + trastuzumab + CAPEOX dose escalation in colorectal cancer; 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.	Drug: ELVN-002; capsule; Drug: Oxaliplatin; intravenous; Drug: Trastuzumab; intravenous; Drug: Capecitabine; capsule
Experimental: Part 2B: ELVN-002 + trastuzumab + mFOLFOX6 dose escalation in colorectal cancer; ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered intravenously in 14-day cycles, 4 mg/kg IV cycle 1, day 2 followed by 2 mg/kg IV cycle 1, day 8, 4mg/kg IV cycle 1, day 15, and then one dose of 4 mg/kg 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.	Drug: ELVN-002; capsule; Drug: Oxaliplatin; intravenous; Drug: Trastuzumab; intravenous; Drug: 5-Fluorouracil; intravenous; Drug: Leucovorin; intravenous
Experimental: Part 2C: ELVN-002 + trastuzumab + capecitabine dose escalation in breast cancer; 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 1250 mg/m2 on days 1 - 14 of a 21-day cycle.	Drug: ELVN-002; capsule; Drug: Trastuzumab; intravenous; Drug: Capecitabine; capsule
Experimental: Part 2D: ELVN-002 + trastuzumab + paclitaxel dose escalation in breast cancer; 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.	Drug: ELVN-002; capsule; Drug: Trastuzumab; intravenous; Drug: paclitaxel; intravenous
Experimental: Part 2E: ELVN-002 + trastuzumab + eribulin dose escalation in breast cancer; 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.	Drug: ELVN-002; capsule; Drug: Trastuzumab; intravenous; Drug: Eribulin; intravenous
Experimental: Part 3A: ELVN-002 + trastuzumab dose expansion in colorectal cancer; 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+	Drug: ELVN-002; capsule; Drug: Trastuzumab; intravenous
Experimental: Part 3B: ELVN-002 + trastuzumab dose expansion in breast cancer; 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+.	Drug: ELVN-002; capsule; Drug: Trastuzumab; intravenous
Experimental: Part 3C: ELVN-002 + trastuzumab dose expansion in other solid tumor type 1; 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+.	Drug: ELVN-002; capsule; Drug: Trastuzumab; intravenous
Experimental: Part 3D: ELVN-002 + trastuzumab dose expansion in other solid tumor type 2; 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+.	Drug: ELVN-002; capsule; Drug: Trastuzumab; intravenous
Experimental: Part 3E: ELVN-002 + trastuzumab dose expansion in other solid tumor type 3; 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+.	Drug: ELVN-002; capsule; Drug: Trastuzumab; intravenous
Experimental: Part 4A: ELVN-002 + trastuzumab + CAPEOX dose expansion in colorectal cancer; 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.	Drug: ELVN-002; capsule; Drug: Oxaliplatin; intravenous; Drug: Trastuzumab; intravenous; Drug: Capecitabine; capsule
Experimental: Part 4B: ELVN-002 + trastuzumab + mFOLFOX6 dose expansion in colorectal cancer; ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered intravenously in 14-day cycles, 4 mg/kg IV cycle 1, day 2 followed by 2 mg/kg IV cycle 1, day 8, 4mg/kg IV cycle 1, day 15, and then one dose of 4 mg/kg 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 days 1 and 15 of a 28-day cycle.	Drug: ELVN-002; capsule; Drug: Oxaliplatin; intravenous; Drug: Trastuzumab; intravenous; Drug: 5-Fluorouracil; intravenous; Drug: Leucovorin; intravenous

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of dose limiting toxicities (DLTs; Phase 1a only)	DLTs will be used to support that the recommended doses for expansion are </= maximum tolerated dose (MTD)	21 days
Incidence of adverse events (AEs)	AEs will be used to support that the recommended doses for expansion are likely to be tolerable	24 months
Incidence of laboratory abnormalities	Clinically significant laboratory abnormalities will be used to support that the recommended doses for expansion are likely to be tolerable	24 months
Incidence of electrocardiogram abnormalities	Clinically significant electrocardiogram abnormalities will be used to support that the recommended doses for expansion are likely to be tolerable	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK parameter of area under the curve of ELVN-002 (Phase 1a only)	The concentration of ELVN-002 measured in the blood over 24 hours at steady state	24 months
PK parameter of maximum concentration of ELVN-002 (Phase 1a only)	The maximum concentration of ELVN-002 measured in the blood at any time point at steady state	24 months
PK parameter of minimum concentration of ELVN-002 (Phase 1a only)	The minimum concentration of ELVN-002 measured in the blood at any time point at steady	24 months
PK parameter of terminal half life of ELVN-002 (Phase 1a only)	The half life of ELVN-002 calculated from the concentration of ELVN-002 measured in blood	24 months
Confirmed objective response rate (ORR)	For patients with measurable disease at baseline, confirmed response as assessed by investigator per RECIST v1.1	24 months
Duration of response (DOR; Phase 1b only)	The time from the first response to progression or death per RECIST v1.1	24 months
Brain metastases response (Phase 1b only)	For patients with measurable brain metastases at baseline, the percent of patients who have a confirmed response per RECIST v1.1	24 months

Collaborators and Investigators

• Sponsor: Enliven Therapeutics

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: March 10, 2024
• First Submitted That Met QC Criteria: March 18, 2024
• First Posted (Actual): March 25, 2024

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: HER2; HER2 overexpression; ELVN-002; HER2 positive Colorectal Cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Breast Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Breast Neoplasms; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Paclitaxel; Trastuzumab; Fluorouracil; Capecitabine; Oxaliplatin; Leucovorin
• Other Study ID Numbers: ELVN-002-003

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No