| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Non-Small Cell Lung Cancer (NSCLC)and Other Solid Tumors with ROS1+ rearrangement |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced Non-Small Cell Lung Cancer and other solid tumors with ROS1+ rearrangement |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
English Phase 1
Primary Objective
• To determine the RP2D and, if applicable, the maximum tolerated dose
(MTD) of NVL-520 in patients with advanced ROS1-positive solid tumors
Phase 2
Primary Objective
• To evaluate the ORR of NVL-520 at the RP2D in patients with advanced
ROS1-positive NSCLC |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1 - Secondary Objectives
• To evaluate the overall safety and tolerability of NVL-520
• To characterize the PK profile of NVL-520
• To evaluate preliminary antitumor activity of NVL-520 in patients with
advanced ROS1 positive solid tumors
Phase 2 - Secondary Objectives
• To assess additional measures of clinical efficacy in patients with
ROS1-positive NSCLC
• To assess clinical efficacy in patients with non-NSCLC ROS1-positive
solid tumors
• To evaluate the intracranial antitumor activity of NVL-520 at the RP2D
in patients with advanced ROS1-positive NSCLC and other solid tumors
• To characterize the safety and tolerability of NVL-520 at the RP2D
• To confirm the PK profile of NVL-520 and metabolite M9 at the RP2D
• To assess treatment-related symptoms and general health status using
validated instruments of patient-reported outcomes (PROs) in patients
treated with NVL-520 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all of the following criteria to be eligible to enroll in the study:
1.Age ≥18 years
a.Phase 2 Cohort 2e only: Age ≥12 years and weighing > 40 kg. (Patients ages 12 to 17 will only be enrolled in countries and at sites where regulations allow.)
2.Disease criteria a.Phase 1: Histologically or cytologically confirmed locally advanced or metastatic solid tumor with documented ROS1 rearrangement, determined by testing in a Clinical Laboratory Improvement Amendments (CLIA) laboratory in the US or equivalently accredited diagnostic lab outside the United States (US) and using a local diagnostic test or a commercial test or by a regulatory agency approved test, such as fluorescence in situ hybridization (FISH) or next generation sequencing (NGS) or reverse transcription polymerase chain reaction (RT-PCR). The report from this test is required to be submitted for eligibility. b.Cohorts 2a, 2b, 2c and 2d: Histologically or cytologically confirmed locally advanced or metastatic NSCLC (excluding patients with transformation to non-NSCLC histology) with ROS1 rearrangement as determined by testing in a CLIA or equivalently accredited diagnostic lab using a local diagnostic test or a commercial test or by a regulatory agency approved test, such as FISH or NGS or RT-PCR. The report from this test is required to be submitted for eligibility. c. Cohort 2e: Histologically or cytologically confirmed locally advanced or metastatic solid tumor (including NSCLC not eligible for Cohorts 2a-2d) with ROS1 rearrangement as determined by testing in a CLIA or equivalently accredited diagnostic lab using a local diagnostic test or a commercial test or by a regulatory agency approved test, such as FISH or NGS or RT-PCR. The report from this test is required to be submitted for eligibility.
3. Prior anticancer treatment a.Phase 1: Patients with ROS1 fusion-positive NSCLC must have previously received at least 1 prior ROS1 TKI, while those with other ROS1-positive solid tumors must have progressed on any prior therapy (includes, but is not limited to, patients who have progressed on prior ROS1 TKIs). Any number of prior platinum-based chemotherapies with or without immunotherapy is allowed.
...
d. Cohort 2c: Must have received 1 prior ROS1 TKI therapy (either crizotinib or entrectinib) and 1 prior platinum-based chemotherapy with or without immunotherapy
...
4. Phase 1: Must have evaluable disease (target or nontarget) according to RECIST 1.1 (Eisenhauer 2009, Appendix 2). Phase 2: Must have measurable disease, defined as ≥1 radiologically measurable target lesion according to RECIST 1.1. Note: Patients with CNS-only disease are eligible, provided that the disease is evaluable (Phase 1) or measurable (Phase 2) and does not meet Exclusion Criterion #11
...
7. Adequate organ function and bone marrow reserve as indicated by the following laboratory values on last assessment prior to the first dose of study drug: a. Bone marrow function: absolute neutrophil count (ANC) ≥1500/µL; platelet count >75,000/µL; hemoglobin ≥8 g/dL (without transfusion).
b. Renal function: estimated creatinine clearance ≥45 mL/min per Cockcroft-Gault formula, modified Cockcroft-Gault formula, or 24 hour creatinine clearance. c.Hepatic function: bilirubin <1.5×ULN, unless evidence of Gilbert Syndrome, in which the patient must have total bilirubin <3.0 mg/dL; aspartate aminotransferase and alanine aminotransferase ≤3.0×ULN (≤5.0×ULN if liver metastases involvement).
8. All clinically relevant toxicities related to prior anticancer therapy must have recovered to Grade ≤1 or baseline (except alopecia or ototoxicity).
9. Women of childbearing potential (WOCBP) must be surgically sterile or be willing to abstain from sexual activity or use a highly effective contraceptive method from the time of signing the informed consent form (ICF) through at least 6 months after the last administration of study drug (or longer, if required by local or country-specific guidance). Male patients with pregnant or non-pregnant WOCBP partners must use male contraception (condom) from the time of signing the ICF through at least 4 months after the last administration of study drug (or longer, if required by local or country-specific guidance). Refer to Section 8.3.2 for acceptable methods of contraception.
10. Provide written informed consent and willing and able to comply with requirements of the study protocol. Phase 2 Cohort 2e only: Assent must be obtained for patients <18 years old (or for minors who have not reached the age of consent, as defined by local regulations) and a parent/guardian must provide written consent.
For the completed list of inclusion criteria please refers to the protocol. |
|
| E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria will be excluded from the study:
1. Patient’s cancer has a known oncogenic driver alteration other than ROS1. For example, NSCLC with a targetable mutation in EGFR, ALK, MET, RET, KRAS or BRAF; colorectal with an oncogenic KRAS, NRAS, or BRAF mutation. Investigators should discuss enrollment with the Sponsor regarding co-mutations.
2. Known allergy/hypersensitivity to excipients of NVL-520.
3. Major surgery within 4 weeks of first dose of study drug. Minor surgical procedures (eg, port insertion) are permitted, but with sufficient time for wound healing as deemed clinically appropriate.
4. Ongoing or recent anticancer therapy within the following timeframe prior to first dose of study drug (NVL-520 may be started within limits for prior TKI or chemotherapy if considered by the Investigator to be safe and within the best interest of the patient, with prior approval from the Sponsor):
a. TKI or other anticancer therapy not listed below in exclusion criteria 4b or 4c: <5 half-lives or <7 days, whichever is longer
b. Chemotherapy, antibody-drug conjugates (ADCs), or other antibodies: <21 days
c. Immunotherapy or cellular therapy <28 days
5. Ongoing or recent radiation therapy within the following timeframe prior to first dose of study drug:
a. Radiation therapy (except palliative radiation to relieve bone pain) <14 days.
b. Palliative radiation to relieve bone pain <48 hours.
c. Stereotactic or small field brain irradiation <7 days.
d. Whole brain radiation <14 days.
6. Prior high-dose chemotherapy requiring stem cell rescue.
7. Uncontrolled clinically relevant bacterial or fungal infection requiring systemic therapy.
8. Has known active tuberculosis or active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg result and known quantitative HBV DNA results greater than the lower limits of detection of the assay. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay.
9. Patient has a QTcF >450 msec (repeated demonstration on more than one assessment). Patient has a history of prolonged QT syndrome or Torsades de pointes.
10. Patients with clinically significant cardiovascular disease as follows:
a. Within 3 months of enrollment: cerebral vascular accident/stroke; myocardial infarction; unstable angina; uncontrolled atrial fibrillation of any grade
b. History of congestive heart failure (New York Heart Association Classification Class ≥II); second-degree or third-degree atrioventricular block (unless paced) or any atrioventricular block with PR consistently >220 msec; or ongoing cardiac dysrhythmias of NCI-CTCAE Grade ≥2.
11. Patient has central nervous system (CNS) metastases or a primary CNS tumor that is associated with progressive neurological symptoms or requires increasing doses of corticosteroids to control the CNS disease. If a patient requires corticosteroids for management of CNS disease, the dose must have been stable for the 2 weeks preceding C1D1. Asymptomatic leptomeningeal carcinomatosis is allowed.
12. Symptomatic spinal cord compression.
13. Patients with moderate to severe cognitive impairment or psychiatric disturbances that would compromise the patient’s ability to comply with study requirements in the Investigator’s opinion.
14. Evidence of active malignancy (other than current ROS1-positive solid malignancy) requiring systemic therapy within the prior 2 years.
a. Exceptions: nonmelanoma skin cancer, in situ melanoma, in situ cervical cancer, papillary thyroid cancer, and localized and presumed cured breast or prostate cancer. Patients on long-term anti-hormonal therapy for a prior malignancy are allowed as long as the malignancy has not been active within the prior 2 years.
15. Concomitant use (within 12 days of first dose of study drug) of strong CYP3A4 inducers or strong CYP3A4 inhibitors (see Appendix 1).
16. Manifestation of malabsorption due to prior gastrointestinal surgery, disease, or other illness that could affect oral absorption, distribution, metabolism, or excretion of the study drug.
17. Patient is pregnant or breastfeeding. WOCBP must have a negative serum pregnancy test at Screening and negative serum or urine test prior to first dose of study drug.
18. Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study.
19. Any medical condition or laboratory abnormality that in the opinion of the Investigator or Sponsor would pose a risk to study patient or confound the ability to interpret study results. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1
• RP2D and, if applicable, the MTD as determined by incidence of DLTs
during Cycle 1, overall safety profile, PK, PD, and preliminary efficacy
Phase 2
• ORR per RECIST 1.1
− Defined as the proportion of patients with a confirmed CR or PR
according to RECIST 1.1 per Blinded Independent Central Review (BICR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Table 1: Schedule of Assessments Phase 1 and Phase 2 (All Cohorts)
Assessments/Procedures
Table 2: Schedule of Pharmacokinetic Sampling Timepoints (Phase 1 and Phase 2)
• DOR per RECIST 1.1
• CBR per RECIST 1.1
• Incidence and severity of TEAEs and changes in clinically relevant
laboratory parameters
• Pharmacokinetic parameters of NVL-520
− Cmax, Cmax - dose normalized, Ctau, Cavg, Tmax, AUCtau, AUCtau -
dose normalized, AUC0-24, AUC0-24 – dose normalized, AUCinf, AUCinf – dose normalized, CL/F, Vz/F, t1/2
• PFS per RECIST 1.1
• Overall survival (OS) |
|
| E.5.2 | Secondary end point(s) |
• Incidence and severity of treatment-emergent adverse events (TEAEs) and changes in clinically relevant laboratory parameters
• Pharmacokinetic parameters of NVL-520
− Maximum plasma concentration (Cmax); Cmax – dose normalized,
plasma concentration at the end of the dosing interval (Ctau); average plasma concentration (Cavg); time of maximum concentration (Tmax); area under the curve at the end of the dosing interval (AUCtau); AUCtau
– dose normalized, area under the curve from time 0 to 24 (AUC0-24); AUC0-24 – dose normalized, area under the curve from time 0 to infinity (AUCinf); AUCinf – dose normalized; oral clearance (CL/F); volume of distribution (Vz/F); and half-life (t1/2)
• Objective response rate (ORR) per Response Evaluation Criteria in
Solid Tumors Version 1.1 (RECIST 1.1)
Phase 2
• DOR per RECIST 1.1
• CBR per RECIST 1.1
• Incidence and severity of TEAEs and changes in clinically relevant
laboratory parameters
• Pharmacokinetic parameters of NVL-520
− Cmax, Cmax - dose normalized, Ctau, Cavg, Tmax, AUCtau, AUCtau -
dose normalized, AUC0-24, AUC0-24 – dose normalized, AUCinf, AUCinf – dose normalized, CL/F, Vz/F, t1/2
• PFS per RECIST 1.1
• Overall survival (OS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Table 1: Schedule of Assessments Phase 1 and Phase 2 (All Cohorts)
Assessments/Procedures
Table 2: Schedule of Pharmacokinetic Sampling Timepoints (Phase 1 and
Phase 2) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Singapore |
| Taiwan |
| Australia |
| Canada |
| Japan |
| Korea, Republic of |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study is defined as the date of the last visit of the last patient in the study or Sponsor’s decision to terminate the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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