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 13, 2024
• Sponsor: Nuvalent Inc.
• Information provided by (Responsible Party): Nuvalent Inc.

Tracking Information

• First Submitted Date: May 17, 2022
• First Posted Date: May 20, 2022
• Last Update Posted Date: May 13, 2024
• Actual Study Start Date: June 9, 2022
• Estimated Primary Completion Date: February 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 8, 2024)

• 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)
• Recommended Phase 2 Dose (RP2D) (Phase 1) [ Time Frame: Within 21 days of last patient dosed during escalation ]
  To determine the RP2D
• Objective Response Rate (ORR) (Phase 2) [ Time Frame: 2-3 years after first patient dosed. ]
  To determine ORR as assessed by BICR
• 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)

Original Primary Outcome Measures (submitted: May 17, 2022)

• 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)
• Recommended Phase 2 Dose (RP2D) [ Time Frame: Within 21 days of last patient dosed during escalation ]
  To determine the RP2D
• Objective Response Rate (ORR) (Phase 2) [ Time Frame: 2-3 years after first patient dosed. ]
  To determine ORR as assessed by BICR

Current Secondary Outcome Measures (submitted: April 8, 2024)

• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Objective response rate (ORR) (Phase 1) [ Time Frame: 2-3 years after first patient dosed ]
  Determine ORR as assessed by BICR
• Duration of response (DOR) [ Time Frame: 2-3 years after first patient dosed ]
  Determine DOR of NVL-655 until radiographic disease progression or death
• Clinical benefit rate (CBR) [ Time Frame: 2-3 years after first patient dosed ]
  Determine CBR of NVL-655
• Time to response [ Time Frame: Approximately 3 years ]
  Determine time to response of NVL-655
• Progression-free survival (PFS) [ Time Frame: 2-3 years after first patient dosed ]
  Determine PFS of NVL-655 until radiographic disease progression or death
• Overall survival (OS) (Phase 2) [ Time Frame: Approximately 3 years ]
  Determine OS
• 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)
• 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.

Original Secondary Outcome Measures (submitted: May 17, 2022)

• Number of participants with treatment-emergent adverse events, as assessed by CTCAE, V5.0 [ Time Frame: Approximately 3 years ]
  Incidence and severity of treatment-emergent adverse events (TEAEs)
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Objective response rate (ORR) (Phase 1) [ Time Frame: 2-3 years after first patient dosed ]
  Determine ORR as assessed by BICR
• Duration of response (DOR) [ Time Frame: 2-3 years after first patient dosed ]
  Determine DOR of NVL-655 until radiographic disease progression or death
• Clinical benefit rate (CBR) [ Time Frame: 2-3 years after first patient dosed ]
  Determine CBR of NVL-655
• Time to response [ Time Frame: Approximately 3 years ]
  Determine time to response of NVL-655
• Progression-free survival (PFS) [ Time Frame: 2-3 years after first patient dosed ]
  Determine PFS of NVL-520 until radiographic disease progression or death
• Overall survival (OS) [ Time Frame: Approximately 3 years ]
  Determine OS

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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.

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 Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Locally Advanced Solid Tumor
• Metastatic Solid Tumor

Intervention

Drug: NVL-655

Oral Tablet of NVL-655

Study Arms

• Experimental: Phase 1 dose escalation
  NVL-655 oral daily dosing
  Intervention: Drug: 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.
  Intervention: Drug: 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.
  Intervention: Drug: 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.
  Intervention: Drug: 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.
  Intervention: Drug: NVL-655
• Experimental: Cohort 2e
  Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, not eligible for other Phase 2 cohorts.
  Intervention: Drug: 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.
  Intervention: Drug: NVL-655

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 8, 2024): 470
• Original Estimated Enrollment (submitted: May 17, 2022): 214
• Estimated Study Completion Date: March 2026
• Estimated Primary Completion Date: February 2026 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Australia, Canada, France, Korea, Republic of, Singapore, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT05384626
• Other Study ID Numbers: NVL-655-01
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Nuvalent Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Nuvalent Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Nuvalent Inc.
• Verification Date: May 2023