| 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 evaluate the overall safety and tolerability of NVL-655
-to determine the RP2D and, if applicable, the MTD of NVL-655 in
patients with advanced ALK-positive solid tumors
Phase 2 Primary Objective(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 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
- To assess treatment-related symptoms and general health status using validated instruments of patient-reported outcomes (PROs) in patients
treated with NVL-655 . |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥18 years
a. Phase 2 Cohort 2f 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 except 2f: 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 2f: 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, and anaplastic thyroid cancer. 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 (ceritinib, alectinib, or brigatinib) as the only prior ALK TKI; no prior investigational agents targeting ALK; ≤ 2 prior lines of chemotherapy
and/or immunotherapy.
c. Phase 2 Cohort 2b: 2-3 prior ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib or lorlatinib; no prior investigational agents targeting ALK; ≤ 2 prior lines of chemotherapy and/or immunotherapy.
d. Phase 2 Cohort 2c: Lorlatinib as the only prior ALK TKI; no prior
investigational agents targeting ALK. Up to 1 prior line of chemotherapy
and/or immunotherapy received prior to lorlatinib is allowed.
e. Phase 2 Cohort 2d: Treatment naïve to ALK TKI therapy. Up to 1 prior line of chemotherapy and/or immunotherapy is allowed.
f. Phase 2 Cohort 2e: Any number of prior ALK TKIs, chemotherapy and/or immunotherapy; not eligible for other Phase 2 cohorts.
g. Phase 2 Cohort 2f: ≥1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists
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 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 at least 4 months after the last administration of study
drug (or longer, if required by local or country-specific guidance). |
|
| 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 halflives
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 quantitative HBV DNA results greater
than the lower limits of detection of the assay. Active Hepatitis C is
defined by a 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; Grade ≥ 3 atrial fibrillation.
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
(excluding atrial fibrillation).
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, or localized and presumed cured breast
or 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):
- Incidence and severity of TEAEs and changes in clinically relevant laboratory parameters
- 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 5.0.1, dated 14 February 2024 |
|
| E.5.2 | Secondary end point(s) |
Phase I Endpoint(s):
- 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
- The incidence of CNS as the first site of disease progression, alone or with concurrent extra-CNS progression
- 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
- Changes in PROs for all patients |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| According to Protocol Version 5.0.1, dated 14 February 2024 |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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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