Clinical trial NCT06328738: ELVN-002 with Trastuzumab +/- Chemotherapy in HER2+ Solid Tumors, Colorectal and Breast Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: HER2-positive Breast Cancer
HER2-positive Gastric Cancer
HER2 Positive Solid Tumors
HER2 Amplification
Colorectal Cancer
Keywords: ELVN-002
HER2 positive Colorectal Cancer
HER2 overexpression
HER2
Lead sponsor: Enliven Therapeutics
Sponsor class: INDUSTRY
First posted: 2024-03-25
Enrollment: 275
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence of dose limiting toxicities (DLTs; Phase 1a only)
timeFrame: 21 days
measure: Incidence of adverse events (AEs)
timeFrame: 24 months
measure: Incidence of laboratory abnormalities
timeFrame: 24 months
measure: Incidence of electrocardiogram abnormalities
timeFrame: 24 months
Secondary outcomes:
measure: PK parameter of area under the curve of ELVN-002 (Phase 1a only)
timeFrame: 24 months
measure: PK parameter of maximum concentration of ELVN-002 (Phase 1a only)
timeFrame: 24 months
measure: PK parameter of minimum concentration of ELVN-002 (Phase 1a only)
timeFrame: 24 months
measure: PK parameter of terminal half life of ELVN-002 (Phase 1a only)
timeFrame: 24 months
measure: Confirmed objective response rate (ORR)
timeFrame: 24 months
measure: Duration of response (DOR; Phase 1b only)
timeFrame: 24 months
measure: Brain metastases response (Phase 1b only)
timeFrame: 24 months
Other outcomes:
Locations:
city: Plantation
country: United States
facility: BRCR Medical Center Inc.
state: Florida
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Fairfax
country: United States
facility: NEXT Virginia
state: Virginia
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Liège
country: Belgium
facility: CHU de Liège
city: Wilrijk
country: Belgium
facility: GZA Ziekenhuizen - Campus Sint-Augustinus
city: Montpellier
country: France
facility: Institut du Cancer de Montpellier - Val D'Aurelle
city: Poitiers
country: France
facility: CHU de Poitiers
city: Saint-Herblain
country: France
facility: Institut de Cancérologie de l'Ouest
city: Strasbourg
country: France
facility: Institut de Cancérologie Strasbourg Europe
city: Catanzaro
country: Italy
facility: Azienda Ospedaliero-Universitaria Renato Dulbecco
city: Milan
country: Italy
facility: Istituto Europeo di Oncologia
city: Monza
country: Italy
facility: Fondazione IRCCS San Gerardo dei Tintori
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana
city: Reggio Emilia
country: Italy
facility: Azienda USL IRCCS di Reggio Emilia
city: Rome
country: Italy
facility: Fondazione Policlinico A. Gemelli IRCCS
city: Seongnam-si
country: Korea, Republic of
facility: CHA Bundang Medical Center
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Soeul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Suwon
country: Korea, Republic of
facility: The Catholic University of Korea, St. Vincent's Hospital
city: Nijmegen
country: Netherlands
facility: Radboud UMC
city: Barcelona
country: Spain
facility: NEXT Oncology-Hospital Quironsalud Barcelona
city: Barcelona
country: Spain
facility: START Barcelona_HM Nou Delfos
city: Barcelona
country: Spain
facility: Hospital Universitari Dexeus - Grupo Quironsalud
city: Barcelona
country: Spain
facility: Instituto de Investigacion Oncologica Vall d'Hebron (VHIO) - EPON
city: Madrid
country: Spain
facility: Hospital Beata Maria Ana
city: Madrid
country: Spain
facility: Clinica universitaria Navarra - Madrid
city: Madrid
country: Spain
facility: START Madrid - Hospital Universitario Fundacion Jimenez Diaz
city: Pamplona
country: Spain
facility: Clinica univeritaria Navarra - Pamplonas
city: Valencia
country: Spain
facility: Fundacion Instituto Valenciano de Oncologia
Study officials:
References: