| 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 ALK rearrangement or activating ALK mutation. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced Non-Small Cell Lung Cancer (NSCLC) and Other Solid Tumors with ALK rearrangement or activating ALK mutation. |
|
| 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 |
Phase 1 Primary Objective(s):
- to determine the RP2D and, if applicable, the MTD of NVL-655 in patients with advanced ALK-positive solid tumors
Phase 2 Primary Onjective(s):
- To evaluate the efficacy of NVL-655 at the RP2D in patients with advanced ALK-positive NSCLC, including those with ALK resistance mutations, and other solid tumors |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1 Secondary Objective(s):
- To evaluate the overall safety and tolerability of NVL-655
- To characterize the PK profile of NVL-655
- To evaluate preliminary antitumor activity of NVL-655 in patients with advanced ALK-positive solid tumors
Phase 2 Secondary Objective(s):
- To assess additional measures of clinical efficacy in patients with ALK-positive NSCLC, including those with ALK resistance mutations, and other solid tumors
- To evaluate the intracranial antitumor activity of NVL-655 at the RP2D in patients with advanced ALK-positive NSCLC and other solid tumors
- To characterize the safety and tolerability of NVL-655 at the RP2D
- To confirm the PK profile of NVL-655 at the RP2D |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥18 years
a. Phase 2 Cohort 2d only: Age ≥12 years and weighing >40 kg. (Patients age 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 a documented ALK rearrangement or activating ALK mutation detected by certified assay (i.e. CLIA in the US). The report from this test is required to be submitted for eligibility.
b. Phase 2 Cohorts 2a, 2b, and 2c: Histologically or cytologically confirmed locally advanced or metastatic NSCLC (excluding patients with documented transformation to non-NSCLC histology) with a documented ALK rearrangement detected by certified assay (i.e. CLIA in the US). The report from this test is required to be submitted for eligibility.
c. Phase 2 Cohort 2d: Any other histologically or cytologically confirmed locally advanced or metastatic solid tumor with a documented ALK rearrangement or activating ALK mutation detected by certified assay, including but not limited to inflammatory myofibroblastic tumors, esophageal squamous cell carcinoma, renal medullary carcinoma, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, papillary thyroid carcinoma, cholangiocarcinoma, spitzoid tumors, neuroblastoma, anaplastic thyroid cancer, and patients with NSCLC not eligible for Cohorts 2a-c. The report from this test is required to be submitted for eligibility
3. Prior anticancer treatment:
a. Phase 1: Patients with ALK fusion-positive NSCLC must have previously received ≥1 ALK TKI, one of which must be a 2nd or 3rd generation TKI (ceritinib, alectinib, brigatinib, or lorlatinib). Patients with other solid tumors must have previously received ≥1 prior systemic anticancer therapy or be those for whom no satisfactory standard therapy exists.
b. Phase 2 Cohort 2a: 1 prior 2nd generation ALK TKI
c. Phase 2 Cohort 2b: 2-3 prior 1st or 2nd generation ALK TKIs (crizotinib, ceritinib, alectinib, or brigatinib)
d. Phase 2 Cohort 2c: 2-3 prior ALK TKIs, with lorlatinib received in the 2nd or 3rd line of therapy
e. Phase 2 Cohort 2d: ≥1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists
f. All patients except Phase 2 Cohort 2d: ≤ 2 prior lines of chemotherapy and/or immunotherapy in the locally advanced or metastatic setting. Patients who have received >2 prior lines of chemotherapy and/or immunotherapy in the locally advanced or metastatic setting may be enrolled in Phase 2 Cohort 2d
g. Phase 2 Cohorts 2a, 2b and 2c: No prior investigational agents targeting ALK. Patients who previously received investigational agents targeting ALK may be enrolled in Phase 1 and Phase 2 Cohort 2d
4. Phase 1: Must have evaluable disease (target or nontarget) according to RECIST 1.1
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
5. Pre-treatment tumor tissue (archived, if available, or a fresh biopsy) submitted for central analysis. It is preferable that submitted tumor tissue be obtained during or after the most recent disease progression. If appropriate tissue is not available, and if biopsy is not considered safe and medically feasible by the Investigator, the patient may be approved for enrollment after consultation with the Sponsor’s Medical Monitor
6. ECOG PS of 0 or 1
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: ANC ≥1500/µL; platelet count >75,000/µL; hemoglobin ≥8 g/dL (without transfusion)
b. Renal function: estimated creatinine clearance ≥60 mL/min
c. Hepatic function: bilirubin <1.5×ULN, unless evidence of Gilbert Syndrome, in which the patient must have total bilirubin <3.0 mg/dL; AST and ALT ≤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. WOCBP and male patients must be surgically sterile or be willing to abstain from sexual activity or use a highly effective contraceptive method (CTFG 2020) from the time of signing the 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 for women, and at least 4 months after the last administration of study drug for men (or longer, if required by local or country-specific guidance). Refer to Section 8.3.2 for acceptable methods of contraception
please refer to the Protocol 4.0 dated 27July 2023. |
|
| E.4 | Principal exclusion criteria |
1. Patient’s cancer has a known oncogenic driver alteration other than ALK. Investigators should discuss enrollment with the Sponsor regarding co-mutations.
2. Known allergy/hypersensitivity to excipients of NVL-655.
3. Major surgery within 4 weeks of the first dose of study drug. Minor surgical procedures (e.g., 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-655 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 non-chemotherapy/non-immunotherapy anticancer agents therapy not listed in exclusion criteria 4b or 4c below: <5 half-lives or <7 days, whichever is longer.
b. Chemotherapy, 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 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 ALK-positive solid malignancy) requiring systemic therapy within the prior 2 years. Exceptions: nonmelanoma skin cancer, in situ melanoma, in situ cervical cancer, papillary thyroid cancer, ductal carcinoma in situ of the breast, or localized and presumed cured prostate cancer. Patients on long-term anti-hormonal therapy for a prior malignancy are allowed if 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.
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. Patient is actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study.
19. Any evidence of current ILD or pneumonitis or a prior history of ILD or non-infectious pneumonitis.
20. 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 Endpoint(s):
- 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 Endpoint(s):
- ORR: Defined as the percent of patients with a CR or PR according to RECIST 1.1 per BICR |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| According to Protocol Version 2.0, dated 25 Mar 2022 |
|
| E.5.2 | Secondary end point(s) |
Phase I Endpoint(s):
- Incidence and severity of TEAEs and changes in clinically relevant laboratory parameters
- PK parameters of NVL-655: 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; and t1/2
- ORR: Defined as the percent of patients with a CR or PR according to RECIST 1.1 per Investigator assessment
- DOR: In responders, defined as the time from first Investigator-assessed response per RECIST 1.1 to radiographic disease progression or death
- IC-ORR: In patients with measurable metastatic CNS disease at baseline, defined as the proportion of patients with a confirmed intracranial response (IC-CR or IC-PR) per investigator, based on assessment of up to 5 intracranial target lesions according to RECIST 1.1 principles
- IC-DOR: In patients with intracranial response, defined as the time from first Investigator-assessed IC-response per RECIST 1.1 to radiographic IC-disease progression or death
- CBR: Defined as the percent of patients with a confirmed CR or PR, or SD of at least 24 weeks duration according to RECIST 1.1 per Investigator assessment
- Time to response: Defined as the time from first dose to first confirmed radiographic response according to RECIST 1.1 per Investigator assessment
- PFS: Defined as the time from first dose to radiographic disease progression per RECIST 1.1 based on Investigator assessment or death.
Phase 2 Endpoint(s):
- DOR: In responders, defined as the time from first BICR-assessed response per RECIST 1.1 to radiographic disease progression or death
- CBR: Defined as the percent of patients with a confirmed CR or PR, or SD of at least 24 weeks duration according to RECIST 1.1 per BICR
- Time to response: Defined as the time from first dose to first confirmed radiographic response according to RECIST 1.1 per BICR assessment
- PFS: Defined as the time from first dose to radiographic disease progression per RECIST 1.1 based on BICR assessment or death
- OS: Defined as the time from first dose to death due to any cause
- IC-ORR: In patients with measurable metastatic CNS disease at baseline, defined as the proportion of patients with a confirmed intracranial response (ICCR or IC-PR) per BICR, based on assessment of up to 5 intracranial target lesions according to RECIST 1.1 principles
- IC-DOR: In patients with intracranial response, defined as the time from first BICR-assessed IC-response per RECIST 1.1 to radiographic IC-disease progression or death
- Time to IC-response: In patients with measurable metastatic CNS disease, defined as the time from first dose to first confirmed radiographic IC-response according to RECIST 1.1 principles per BICR
- IC-PFS: In patients with measurable metastatic CNS disease, defined as the time from first dose to intracranial radiographic disease progression per RECIST 1.1 principles based on BICR assessment or death
- Incidence and severity of TEAEs and changes in clinically relevant laboratory parameters
- PK parameters of NVL-655: 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| According to Protocol Version 2.0, dated 25 Mar 2022 |
|
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| 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 | Yes |
| 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 |
| Switzerland |
| 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.
If supported by clinical rationale, adequate drug supply, and establishment of appropriate mechanisms for continued provision of NVL-655, patients who are deriving clinical benefit at study closure or termination may continue to receive NVL-655 until disease progression or commercial availability of NVL-655. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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