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

PHASE1PHASE2RECRUITING

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.

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Study details:

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.

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Eligibility criteria

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Inclusion criteria

Age ≥18 years, Phase 2 Cohort 2f only: Age ≥12 years and weighing >40 kg.

Phase 1: Histologically or cytologically confirmed locally advanced or metastatic solid tumor with a documented ALK rearrangement or activating ALK mutation.

Phase 2

Phase 2 Cohorts except 2f: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with a documented ALK rearrangement

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.

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

Adequate organ function and bone marrow reserve

Exclusion criteria

Patient's cancer has a known oncogenic driver alteration other than ALK.

Known allergy/hypersensitivity to excipients of NVL-655.

Major surgery within 4 weeks of the study entry

Ongoing or anticancer therapy

Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study.

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Eligibility

Age eligible for study : 12 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2022-06-09

Primary completion: 2026-02-01

Study completion finish: 2026-03-01

Study type

TREATMENT

Phase

PHASE1

PHASE2

Trial ID

NCT05384626

Intervention or treatment

DRUG: NVL-655

Conditions

• Locally Advanced Solid Tumor
• Metastatic Solid Tumor

Image related to Locally Advanced Solid Tumor

Condition: Locally Advanced Solid Tumor, Metastatic Solid Tumor
DRUG: NVL-655
Woolloongabba, Queensland, Australia and more
Sponsor: Nuvalent Inc.

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Find a site

Closest Location:

Princess Alexandra Hospital

Research sites nearby

Select from list below to view details:

Princess Alexandra Hospital
Woolloongabba, Queensland, Australia
Peter MacCallum Cancer Centre
Melbourne, Victoria, Australia
Royal North Shore Hospital
Saint Leonards, New South Wales, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/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

What is the study measuring?

Primary outcome

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

Secondary outcome

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

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References

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