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A Study of NVL-520 in Patients With Advanced NSCLC and Other Solid Tumors Harboring ROS1 Rearrangement (ARROS-1)

PHASE1PHASE2RECRUITING

Phase 1/2, dose escalation and expansion study designed to evaluate the safety and tolerability of NVL-520, determine the recommended phase 2 dose (RP2D), and evaluate the antitumor activity in patients with advanced ROS1-positive (ROS1+) NSCLC and other advanced ROS1-positive solid tumors. Phase 1 will determine the RP2D and, if applicable, the maximum tolerated dose (MTD) of NVL-520 in patients with advanced ROS1-positive solid tumors. Phase 2 will determine the objective response rate (ORR) as assessed by Blinded Independent Central Review (BICR) of NVL-520 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-520 in patients with advanced ROS1-positive NSCLC and other solid tumors.

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Study details:

In Phase 2, study patients will be enrolled into 5 distinct expansion cohorts:. * Cohort 2a: ROS1-positive NSCLC naïve to Tyrosine Kinase Inhibitor (TKI) therapy and up to 1 prior chemotherapy and/or immunotherapy. * Cohort 2b: ROS1-positive NSCLC treated with 1 prior ROS1 TKI and no prior chemotherapy or immunotherapy.

* Cohort 2c: ROS1-positive NSCLC treated with 1 prior ROS1 TKI and 1 prior platinum-based chemotherapy with or without immunotherapy. * Cohort 2d: ROS1-positive NSCLC treated with ≥2 prior ROS1 TKIs and up to 1 prior chemotherapy and/or immunotherapy. * Cohort 2e: ROS1-positive solid tumor and progressed on any prior therapy.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Age ≥18 years (Cohort 2e only: Age ≥12 years and weighing>40 kg).

Phase 1: Histologically or cytologically confirmed locally advanced or metastatic solid tumor with documented ROS1 rearrangement.

Phase 2: Cohorts 2a, 2b, 2c and 2d: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with ROS1 rearrangement.

Phase 2: Cohort 2e: Histologically or cytologically confirmed locally advanced or metastatic solid tumor (other than NSCLC) with ROS1 rearrangement.

Prior anticancer treatment (except cohort 2a).

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 baseline organ function and bone marrow reserve.

Exclusion criteria

Patient's cancer has a known oncogenic driver alteration other than ROS1.

Known allergy/hypersensitivity to excipients of NVL-520.

Major surgery within 4 weeks of first dose of study drug.

Ongoing 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: 2022-01-04

Primary completion: 2025-10-31

Study completion finish: 2026-10-31

Study type

TREATMENT

Phase

PHASE1

PHASE2

Trial ID

NCT05118789

Intervention or treatment

DRUG: NVL-520

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-520
Camperdown, New South Wales, Australia and more
Sponsor: Nuvalent Inc.

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Find a site

Closest Location:

Chris O'Brien Lifehouse

Research sites nearby

Select from list below to view details:

Chris O'Brien Lifehouse
Camperdown, New South Wales, Australia
Peter MacCallum Cancer Centre
Melbourne, Victoria, 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-520 oral daily dosing	DRUG: NVL-520 Oral tablet of NVL-520
EXPERIMENTAL: Cohort 2a ROS1+ NSCLC naïve to TKI therapy and up to 1 prior chemotherapy and/or immunotherapy	DRUG: NVL-520 Oral tablet of NVL-520
EXPERIMENTAL: Cohort 2b ROS1+ NSCLC treated with 1 prior ROS1 TKI and no prior chemotherapy or immunotherapy	DRUG: NVL-520 Oral tablet of NVL-520
EXPERIMENTAL: Cohort 2c ROS1+ NSCLC treated with 1 prior ROS1 TKI and 1 prior platinum-based chemotherapy with or without immunotherapy	DRUG: NVL-520 Oral tablet of NVL-520
EXPERIMENTAL: Cohort 2d ROS1+ NSCLC treated with ≥2 prior ROS1 TKIs and up to 1 prior chemotherapy and/or immunotherapy	DRUG: NVL-520 Oral tablet of NVL-520
EXPERIMENTAL: Cohort 2e ROS1+ solid tumor and progressed on any prior therapy	DRUG: NVL-520 Oral tablet of NVL-520

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Maximum Tolerated Dose (MTD) (Phase 1)	Highest dose with dose-limiting toxicity (DLT) rate ≤ 25%	Within 28 days of last patient dosed during dose escalation
Recommended Phase 2 Dose (RP2D)	To determine the RP2D	Within 28 days of last patient dosed during dose escalation.
Objective Response Rate (ORR) (Phase 2)	To determine ORR as assessed by BICR	2-3 years after first patient dosed.

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Number of participants with treatment-emergent adverse events, as assessed by CTCAE, v5.0	Incidence and severity of treatment-emergent adverse events (TEAEs)	Approximately 3 years.
Maximum plasma concentration (Cmax) of NVL-520	To determine the maximum plasma concentration (Cmax) of NVL-520	Pre-dose and up to 24 hours post-dose
Plasma concentration at the end of the dosing interval (Ctau) of NVL-520	To determine the plasma concentration at the end of the dosing interval (Ctau) of NVL-520	Pre-dose and up to 24 hours post-dose
Average plasma concentration (Cavg) of NVL-520	To determine the average plasma concentration (Cavg) of NVL-520	Pre-dose and up to 24 hours post-dose
Time of maximum concentration (Tmax) of NVL-520	To determine the time of maximum concentration (Tmax) of NVL-520	Pre-dose and up to 24 hours post-dose
Area under the curve at the end of the dosing interval (AUCtau) of NVL-520	To determine the area under the curve at the end of the dosing interval (AUCtau) of NVL-520	Pre-dose and up to 24 hours post-dose
Area under the curve from time 0 to 24 (AUC0-24) of NVL-520	To determine the area under the curve from time 0 to 24 (AUC0-24) of NVL-520	Pre-dose and up to 24 hours post-dose
Area under the curve from time 0 to infinity (AUCinf) of NVL-520	To determine the area under the curve from time 0 to infinity (AUCinf) of NVL-520	Pre-dose and up to 24 hours post-dose
Oral clearance (CL/F) of NVL-520	To determine the oral clearance (CL/F) of NVL-520	Pre-dose and up to 24 hours post-dose
Volume of distribution (Vz/F) of NVL-520	To determine the volume of distribution (Vz/F) of NVL-520	Pre-dose and up to 24 hours post-dose
Half-life (t1/2) of NVL-520	To determine the half-life (t1/2) of NVL-520	Pre-dose and up to 24 hours post-dose
Objective response rate (ORR)	Determine ORR as assessed by BICR	2-3 years after first patient dosed
Duration of response (DOR)	Determine DOR of NVL-520 until radiographic disease progression or death	2-3 years after first patient dosed
Clinical benefit rate (CBR)	Determine CBR of NVL-520	2-3 years after first patient dosed
Time to response	Determine time to response of NVL-520	2-3 years after first patient dosed
Progression-free survival (PFS)	Determine PFS of NVL-520 until radiographic disease progression or death	Approximately 3 years
Overall survival (OS)	Determine OS	Approximately 3 years
Rate of CNS progression	The incidence of CNS as first site of progression, alone or with concurrent extra-CNS progression	Approximately 3 years
Intracranial objective response rate (IC-ORR)	Determine the intracranial objective response rate	Approximately 3 years
Quality of life assessment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)	EORTC QLQ-C30 measures cancer patients' physical, psychological, and social functions. Scale ranges from: 1, "Not at all"; 2, "A little"; 3, "Quite a bit"; to 4, "Very much." Higher score for the functioning scales and global health status denotes a better level of functioning, while higher scores on the symptom and single-item scales indicate a higher level of symptoms.	2-3 years after first patient dosed
Quality of life assessment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer 29 module (EORTC QLQ-LC29)	EORTC-QLQ-LC29 measures the quality of life in patients with lung cancer. Symptom scale ranges from: 1, "Not at all"; 2, "A little"; 3, "Quite a bit"; to 4, "Very much." For symptoms scales, higher scores indicated greater symptom burden.	2-3 years after first patient dosed

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References

Clinical Trials Gov: A Study of NVL-520 in Patients With Advanced NSCLC and Other Solid Tumors Harboring ROS1 Rearrangement (ARROS-1)