A Study of NVL-655 in Patients With Advanced NSCLC and Other Solid Tumors Harboring ALK Rearrangement or Activating ALK Mutation (ALKOVE-1)

• ClinicalTrials.gov Identifier: NCT05384626
• Recruitment Status: Recruiting
• First Posted: May 20, 2022
• Last Update Posted: May 8, 2024
• Sponsor: Nuvalent Inc.
• Information provided by (Responsible Party): Nuvalent Inc.

Study Description

Brief Summary:

Phase 1/2, dose escalation and expansion study designed to evaluate the safety and tolerability of NVL-655, determine the recommended phase 2 dose (RP2D), and evaluate the antitumor activity in patients with advanced ALK- positive (ALK+) NSCLC and other solid tumors.

Phase 1 will evaluate the overall safety and tolerability of NVL-655 and will determine the RP2D and, if applicable, the MTD of NVL-655 in patients with advanced ALK+ solid tumors.

Phase 2 will determine the objective response rate (ORR) as assessed by Blinded Independent Central Review (BICR) of NVL-655 at the RP2D. Secondary objectives will include the duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and clinical benefit rate (CBR) of NVL-655 in patients with advanced ALK-positive NSCLC and other solid tumors.

Condition or disease	Intervention/treatment	Phase
Locally Advanced Solid Tumor; Metastatic Solid Tumor	Drug: NVL-655	Phase 1; Phase 2

Detailed Description:

In Phase 2, study patients will be enrolled into 6 distinct cohorts:

• Cohort 2a: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have received 1 prior 2nd-generation ALK TKI (ceritinib, alectinib, or brigatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.
• Cohort 2b: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received 2-3 prior ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.
• Cohort 2c: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received lorlatinib as the only prior ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy received prior to lorlatinib is allowed.
• Cohort 2d: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who are naïve to ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy is allowed.
• Cohort 2e: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, not eligible for other Phase 2 cohorts.
• Cohort 2f: Patients with other solid tumors harboring an ALK rearrangement or activating ALK mutation, who have received ≥1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 470 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2 Study of the Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor NVL-655 in Patients With Advanced NSCLC and Other Solid Tumors (ALKOVE-1)
• Actual Study Start Date: June 9, 2022
• Estimated Primary Completion Date: February 2026
• Estimated Study Completion Date: March 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1 dose escalation; NVL-655 oral daily dosing	Drug: NVL-655; Oral Tablet of NVL-655
Experimental: Cohort 2a; Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have received 1 prior 2nd-generation ALK TKI (ceritinib, alectinib, or brigatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.	Drug: NVL-655; Oral Tablet of NVL-655
Experimental: Cohort 2b; Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received 2-3 prior ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.	Drug: NVL-655; Oral Tablet of NVL-655
Experimental: Cohort 2c; Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received lorlatinib as the only prior ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy received prior to lorlatinib is allowed.	Drug: NVL-655; Oral Tablet of NVL-655
Experimental: Cohort 2d; Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who are naïve to ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy is allowed.	Drug: NVL-655; Oral Tablet of NVL-655
Experimental: Cohort 2e; Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, not eligible for other Phase 2 cohorts.	Drug: NVL-655; Oral Tablet of NVL-655
Experimental: Cohort 2f; Patients with other solid tumors harboring an ALK rearrangement or activating ALK mutation, who have received ≥1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists.	Drug: NVL-655; Oral Tablet of NVL-655

Outcome Measures

Primary Outcome Measures :

1. Dose limiting toxicities (DLTs) (Phase 1) [ Time Frame: Within the first 21 days of the first NVL-655 dose ]
   Define the dose limiting toxicities (DLTs)
2. Recommended Phase 2 Dose (RP2D) (Phase 1) [ Time Frame: Within 21 days of last patient dosed during escalation ]
   To determine the RP2D
3. Objective Response Rate (ORR) (Phase 2) [ Time Frame: 2-3 years after first patient dosed. ]
   To determine ORR as assessed by BICR
4. Number of participants with treatment-emergent adverse events, as assessed by CTCAE, V5.0 (Phase 1) [ Time Frame: Approximately 3 years ]
   Incidence and severity of treatment-emergent adverse events (TEAEs)

Secondary Outcome Measures :

1. Maximum plasma concentration, (Cmax) of NVL-655 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
   To determine the maximum plasma concentration (Cmax) of NVL
2. Plasma concentration at the end of the dosing interval (Ctau) of NVL-655 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
   To determine the plasma concentration at the end of the dosing interval (Ctau) of NVL-655
3. Average plasma concentration (Cavg) of NVL-655 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
   To determine the average plasma concentration (Cavg) of NVL-655
4. Time of maximum concentration (Tmax) of NVL-655 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
   To determine the time of maximum concentration (Tmax) of NVL-655
5. Area under the curve at the end of the dosing interval (AUCtau) of NVL-655 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
   To determine the area under the curve at the end of the dosing interval (AUCtau) of NVL-655
6. Area under the curve from time 0 to 24 (AUC0-24) of NVL-655 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
   To determine the area under the curve from time 0 to 24 (AUC0-24) of NVL-655
7. Area under the curve from time 0 to infinity (AUCinf) of NVL-655 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
   To determine the area under the curve from time 0 to infinity (AUCinf) of NVL-655
8. Oral clearance (CL/F) of NVL-655 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
   To determine the oral clearance (CL/F) of NVL-655
9. Volume of distribution (Vz/F) of NVL-655 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
   To determine the volume of distribution (Vz/F) of NVL-655
10. Half-life (t1/2) of NVL-655 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
    To determine the half-life (t1/2) of NVL-655
11. Objective response rate (ORR) (Phase 1) [ Time Frame: 2-3 years after first patient dosed ]
    Determine ORR as assessed by BICR
12. Duration of response (DOR) [ Time Frame: 2-3 years after first patient dosed ]
    Determine DOR of NVL-655 until radiographic disease progression or death
13. Clinical benefit rate (CBR) [ Time Frame: 2-3 years after first patient dosed ]
    Determine CBR of NVL-655
14. Time to response [ Time Frame: Approximately 3 years ]
    Determine time to response of NVL-655
15. Progression-free survival (PFS) [ Time Frame: 2-3 years after first patient dosed ]
    Determine PFS of NVL-655 until radiographic disease progression or death
16. Overall survival (OS) (Phase 2) [ Time Frame: Approximately 3 years ]
    Determine OS
17. Number of participants with treatment-emergent adverse events, as assessed by CTCAE, V5.0 (Phase 2) [ Time Frame: Approximately 3 years ]
    Incidence and severity of treatment-emergent adverse events (TEAEs)
18. Quality of life assessment [ Time Frame: 2-3 years after first patient dosed ]
    Measure the quality of life in patients with cancer and/or lung cancer.

Eligibility Criteria

• Ages Eligible for Study: 12 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age ≥18 years, Phase 2 Cohort 2f only: Age ≥12 years and weighing >40 kg.
2. Phase 1: Histologically or cytologically confirmed locally advanced or metastatic solid tumor with a documented ALK rearrangement or activating ALK mutation.

3. Phase 2

   1. Phase 2 Cohorts except 2f: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with a documented ALK rearrangement
   2. Phase 2 Cohort 2f: Histologically or cytologically confirmed locally advanced or metastatic solid tumor with a documented ALK rearrangement or activating ALK mutation detected by certified assay.
4. Phase 1: Must have evaluable disease (target or nontarget) according to RECIST 1.1 Phase 2: Must have measurable disease according to RECIST 1.1
5. Adequate organ function and bone marrow reserve

Exclusion criteria:

1. Patient's cancer has a known oncogenic driver alteration other than ALK.
2. Known allergy/hypersensitivity to excipients of NVL-655.
3. Major surgery within 4 weeks of the study entry
4. Ongoing or anticancer therapy
5. Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study.

Contacts and Locations

Contacts

Contact: Tina Kehrig; 857-357-7000; clinicaltrials@nuvalent.com

Locations

United States, California

University of California Irvine Medical Center; Recruiting

Orange, California, United States, 92868

Principal Investigator: Misako Nagasaka, MD

University of California, Davis Comprehensive Cancer Center; Recruiting

Sacramento, California, United States, 95817

Principal Investigator: Jonathan Riess, MD

Stanford Cancer Institute; Recruiting

Stanford, California, United States, 94305

Principal Investigator: Joel Neal, MD, PhD

United States, Colorado

University of Colorado Cancer Center; Recruiting

Denver, Colorado, United States, 80045

Principal Investigator: Ross Camidge, MD, PhD

United States, District of Columbia

Georgetown University Medical Center; Recruiting

Washington, District of Columbia, United States, 20007

Principal Investigator: Joshua Reuss, MD

United States, Florida

University of Miami; Sylvester Cancer Center; Recruiting

Miami, Florida, United States, 33136

Principal Investigator: Gilberto de Lima Lopes, MD

United States, Maryland

John Hopkins University; Recruiting

Baltimore, Maryland, United States, 21224

Principal Investigator: VIncent Lam, MD

United States, Massachusetts

Mass General Hospital; Active, not recruiting

Boston, Massachusetts, United States, 02114

United States, Michigan

Henry Ford Cancer Institute; Recruiting

Detroit, Michigan, United States, 48202

Principal Investigator: Shirish Gadgeel, MD

United States, Missouri

Washington University School of Medicine Siteman Cancer Center; Recruiting

Saint Louis, Missouri, United States, 63310

Principal Investigator: Saiama Waqar, MD

United States, New York

Laura & Isaac Perlmutter Cancer Center at NYU Langone Health; Recruiting

New York, New York, United States, 10016

Principal Investigator: Sally Lau, MD

Memorial Sloan Kettering Cancer Center; Recruiting

New York, New York, United States, 10065

Principal Investigator: Alexander Drilon, MD

United States, North Carolina

Duke University Medical Center; Recruiting

Durham, North Carolina, United States, 27710

Principal Investigator: Thomas Stinchcombe, MD

United States, Ohio

OSU Brain & Spine Hospital; Recruiting

Columbus, Ohio, United States, 43210

Principal Investigator: Logan Roof, MD, MSCR

United States, Tennessee

Sarah Cannon; Recruiting

Nashville, Tennessee, United States, 37203

Principal Investigator: Melissa Johnson, MD

United States, Texas

MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Principal Investigator: George Blumenschein, MD

United States, Washington

Fred Hutchinson Cancer Center; Recruiting

Seattle, Washington, United States, 98109

Principal Investigator: Christina Baik, MD, MPH

Australia, New South Wales

Royal North Shore Hospital; Recruiting

Saint Leonards, New South Wales, Australia, 2065

Principal Investigator: Nick Pavlakis, MD, PhD

Australia, Queensland

Princess Alexandra Hospital; Recruiting

Woolloongabba, Queensland, Australia, 4102

Principal Investigator: Kenneth O'Byrne, MD

Australia, Victoria

Peter MacCallum Cancer Centre; Recruiting

Melbourne, Victoria, Australia, 3000

Principal Investigator: Benjamin Solomon, MD, PhD

Canada, Alberta

Cross Cancer Institute; Active, not recruiting

Edmonton, Alberta, Canada, T6G 1Z2

Canada, Ontario

Princess Margaret Cancer Centre; Active, not recruiting

Toronto, Ontario, Canada, M5G 0A3

France

Centre Leon Berard; Active, not recruiting

Lyon, France, 69373

Chu De Nantes; Active, not recruiting

Saint-Herblain, France, 44800

Institut Claudius Regaud; Active, not recruiting

Toulouse Cedex, France, 31059

Institute Gustave Roussy; Active, not recruiting

Villejuif, France, 94805

Korea, Republic of

National Cancer Center; Recruiting

Goyang-si, Gyeonggi-do, Korea, Republic of, 10408

Principal Investigator: Ji-Youn Han, MD

Seoul National University Hospital; Recruiting

Seoul, Seoul Capital, Korea, Republic of, 03080

Principal Investigator: Dong-wan Kim, MD

Severance Hospital Yonsei University Health System; Recruiting

Seoul, Seoul Capital, Korea, Republic of, 03722

Principal Investigator: Byoung Chul Cho, MD

Singapore

National Cancer Centre Singapore; Recruiting

Singapore, Singapore, 168583

Principal Investigator: Aaron Tan, MD

Spain

Complejo Hospitalario Universitario de A Coruna; Recruiting

A Coruña, Spain, 15006

Principal Investigator: Maria Campelo, MD

UOMI Cancer Center; Recruiting

Barcelona, Spain, 08017

Principal Investigator: Santiago Viteri Ramirez, PhD

Vall d'Hebron; Recruiting

Barcelona, Spain, 08035

Principal Investigator: Enriqueta Felip, Md, PhD

Hospital General Universitario Gregorio Maranon; Recruiting

Madrid, Spain, 28007

Principal Investigator: Antonio Calles, MD

Hospital Universitario 12 de Octubre; Recruiting

Madrid, Spain, 28041

Principal Investigator: Luis Paz Ares, MD, PhD

United Kingdom

Royal Marsden Hospital; Recruiting

Sutton, Surrey, United Kingdom, SM2 5PT

Principal Investigator: Anna Minchom, MB BCh MRCP MD

The Christie NHS Foundation Trust; Recruiting

Manchester, United Kingdom, M20 4BX

Principal Investigator: Matthew Krebs, PhD

Sponsors and Collaborators

Nuvalent Inc.

Investigators

• Study Director: Viola Zhu, MD, PHD; Nuvalent Inc.

More Information

• Responsible Party: Nuvalent Inc.
• ClinicalTrials.gov Identifier: NCT05384626
• Other Study ID Numbers: NVL-655-01
• First Posted: May 20, 2022
• Last Update Posted: May 8, 2024
• Last Verified: May 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Neoplasms