| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Non-Small Cell Lung Cancer (NSCLC) harboring (mesenchymal-epithelial transition) MET Exon 14 skipping mutations; NSCLC harboring MET
amplification; Pan-cancers (solid tumors) harboring MET amplification; Pan cancers (solid tumors) harboring MET fusion; Primary central
nervous system (CNS) tumors harboring MET alterations |
|
| E.1.1.1 | Medical condition in easily understood language |
A solid tumor carrying MET dysregulated genetic alterations or NonSmall Cell Lung Cancer (NSCLC) carrying MET EXON 14 skip mutations,
central nervous system tumors |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10007958 |
| E.1.2 | Term | Central nervous system neoplasm |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The objectives of the completed Phase 1 of the study were:
-To assess overall safety and tolerability
-To determine the dose-limiting toxicities (DLTs)
-To identify the RP2D
-To determine the pharmacokinetic (PK) parameters of orally administered APL-101
-To obtain preliminary efficacy in subjects with MET dysregulation in advanced malignancies and non-small cell lung cancer (NSCLC).
Phase 2 Primary Objective:
To assess efficacy of APL-101 as monotherapy for the treatment of:
-NSCLC harboring (mesenchymal-epithelial transition) MET Exon 14 skipping mutations
-NSCLC harboring MET amplification
-Pan-cancers (solid tumors) harboring MET amplification
-Pan cancers (solid tumors) harboring MET fusion
-Primary central nervous system (CNS) tumors harboring MET alterations
-Pan-cancers (solid tumors) harboring wild-type MET with overexpression of HGF and MET
-To assess APL-101 as an add-on therapy to EGFR inhibitor for the treatment of NSCLC harboring EGFR activating mutations |
|
| E.2.2 | Secondary objectives of the trial |
Phase 2 Secondary Objective:
- To assess the safety and tolerability of APL-101 as monotherapy
- To assess the safety and tolerability of APL-101 as an add-on therapy to an EGFR-I
- PK assessments
Phase 1/2 Exploratory Objective:
- To evaluate potential pharmacodynamic (PD) biomarkers of APL-101 and its correlation to the PK profile.
- To evaluate relationship of relevant biomarkers, including MET protein expression, amplification, and/or mutations to clinical response.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent
before any study-specific procedure is performed.
2. 18 years of age or older.
3. For Phase 1, histologically and / or cytologically confirmed unresectable or metastatic solid malignancy, refractory to standard
therapies with no more than three prior lines of therapy
4.For Phase 2, nine cohorts will be enrolled: Cohort A-1 (all countries except Finland); Cohort A-2; Cohort B (Enrollment Completed); Cohort C; Cohort C-1; Cohort C-2, Cohort D, Cohort E and Cohort F; For detailed Cohort information please refer to the Protocol Amdt 10 dated 11AUG2023
5. In Phase 2, provision of sample e.g. archival or a fresh tumor biopsy sample (if safe and feasible) either from the primary or a metastatic site or liquid biopsy sample (if tumor tissue insufficient or lacking, and approved by the sponsor) is required for prospective central lab confirmation for study entry.
6. Treated or untreated asymptomatic parenchymal CNS disease or leptomeningeal disease is allowed.
7. Presence of ≥1 measurable lesion (scan done <=28 days of C1D1) to
serve as target lesion according to relevant criteria (RECIST v1.1, RANO for CNS tumors, or other relevant criteria per tumor type) prospectively
confirmed by the Independent Review Committee (IRC).
8. ECOG performance status of 0–1. For subjects with primary CNS tumors, KPS score ≥70.
9. Acceptable organ function, as evidenced by the following laboratory data during Screening period:
a. Aspartate aminotransferase (AST) and alanine aminotransferase
(ALT) ≤ 2.5 x ULN.
b. Total serum bilirubin ≤ 1.5 x ULN.
c. For subjects with liver metastases: total bilirubin ≤ 3.0 x ULN, AST/
ALT ≤ 5 x ULN.
d.Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 (1.5 x 109/L).
e.Platelet count ≥ 100,000 cells/mm3 (100 x 109/L).
f. Serum creatinine levels ≤ 1.5 ULN or creatinine clearance (CrCl) ≥ 60 mL/min as calculated by the Cockcroft-Gault method
g. Hemoglobin ≥ 9 g/dL.
10. For all prior anticancer treatment, including radiotherapy, chemotherapy or targeted agents (except EGFR-I for Cohort C2) or hormonal therapy, a duration of 30 days or 5 half-lives of the agents used, whichever is shorter, must have elapsed, and any encountered toxicity must have resolved to levels meeting all the other eligibility criteria prior to the first dose of study treatment. Palliative radiotherapy to non target lesions should be completed within 2 weeks prior to APL-101 administration. Subjects with glioblastoma (GBM) on Optune® therapy may be allowed if the following criteria are met: Must agree to switch off Optune ® at least 3 days prior to C1D1 and during the study; All AEs associated with Optune ® use must be resolved to Grade ≤ 1 at least 3 days prior to C1D1. An MRI/CT scan is performed after discontinuation of Optune ®.
11. Adequate cardiac function with left ventricular ejection fraction (LVEF) ≥ 50% at screening.
12. Women of child-bearing potential (WOCBP) must have a negative serum or β-human chorionic gonadotropin (β-hCG) or evidence of postmenopausal status.
13. All subjects with reproductive potential must agree to use of effective contraceptive measures
14. Resolution of all chemotherapy, radiotherapy or surgery-related AEs to Grade ≤ 1, except for alopecia. Subjects who experienced significant
complications with prior immuno-oncology (IO) therapy or EGFR-Inhibitor therapy or Grade 3 or higher LFT abnormalities or QT abnormalities will not qualify to participate.
15. No planned major surgery within 4 weeks of first dose of APL-101.
16. Willing and able to participate in all required evaluations and procedures in this study.
17. Expected survival (life expectancy) ≥ 3 months from C1D1.
NOTE: Subjects with more than one MET alteration are allowed to enroll if meeting at least one of the alterations defined for the specific cohort.
•If a subject with NSCLC meets both MET Exon 14 skipping mutations and amplification or both MET Exon 14 skipping mutations and fusion
criteria, the subject should be enrolled in Cohort A-1, A-2, or B, as appropriate, based on prior therapy use
•If a subject with a solid tumor (including NSCLC) meets both MET amplification and MET fusion criteria, the subject should be enrolled in
Cohort D
•If a subject with a solid tumor (excluding NSCLC and primary CNS tumors) meets both MET Exon 14 skipping mutations and amplification,
the subject should be enrolled in Cohort D with MET Exon 14 skipping mutations noted as MET-MET fusion.
•For Cohorts C and C-1, MET Exon 14 skipping mutations or fusion are excluded; however, it will be acceptable to carry other MET alterations
(e.g., non-Exon 14 skipping mutations).
•For Cohort F, MET Exon 14 skipping mutations or fusion or amplification are excluded; however, it will be acceptable to carry other MET
alterations (e.g., non-Exon 14 skipping mutations). |
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following exclusion criteria will be excluded
from the study:
1. Hypersensitivity to APL-101, excipients of the drug product, or other components of the study treatment regimen.
2. Known actionable mutation/gene rearrangement of EGFR (except for NSCL subjects Cohort C and C-2), ALK, ROS1, RET, NTRK, KRAS, and BRAF.
3. Use or intended use of any other investigational product, including herbal medications, through Study Treatment Termination.
4. Active uncontrolled systemic bacterial, viral, or fungal infection or clinically significant, active disease process, which in the opinion of the
investigator makes the risk: benefit unfavorable for the participation of the trial. Screening for chronic conditions is not required.
5. Life-threatening illness, significant organ system dysfunction or comorbid conditions, or other reasons that, in the investigator's opinion,
could compromise the subject's safety or the integrity of the study outcomes, or interfere with the absorption or metabolism of APL-101.
6. Unstable angina or myocardial infarction within 1 year prior to first dose of APL-101, symptomatic or unstable arrhythmia requiring medical
therapy, history of congenital prolonged QT syndrome, prolonged QT interval corrected by Fridericia formula (QTcF) at screening (> 450 msec
based on the average of 3 measurements), or concurrent treatment with a medication that is a known risk for prolonging the QT interval. Chronic controlled atrial fibrillation is not excluded.
7. Historical seropositive results consistent with active infection for hepatitis C virus (HCV) or hepatitis B virus (HBV) with high viral loads
not actively managed with antiviral therapy and human immunodeficiency virus (HIV) positive subjects who are not clinically
stable or controlled on their medication (asymptomatic subjects with CD4+ T-cell (CD4+) counts ≥ 350 cells/µL and have not had an
opportunistic infection within the past 12 months prior to first dose of APL-101 would be eligible for study entry. If history is unclear, relevant
test(s) at Screening will be required to confirm eligibility.
8. Known significant mental illness or other conditions such as active alcohol or other substance abuse that, in the opinion of the investigator,
predisposes the subject to high risk of noncompliance with the protocol treatment or assessments.
9. Unable to swallow orally administered medication whole.
10. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter drug absorption (e.g., Crohn's, ulcerative
colitis, active inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
11. Women who are breastfeeding.
12. History of another malignancy within 3 years prior to C1D1. A subject with the following malignancies is allowed if considered cured or
unlikely to recur within 3 years:
a. Carcinoma of the skin without melanomatous features.
b. Curatively treated cervical carcinoma in situ.
c. Bladder tumors considered superficial such as noninvasive (T1a) and carcinoma in situ (T1s), thyroid papillary cancer with prior treatment,
prostate cancer which has been surgically or medically treated and not likely to recur within 3 years.
13. Subjects who are unable or unwilling to discontinue excluded medications (drugs with known QTc risk and known strong cytochrome
P450 [CYP]3A4 inducer and/or strong inhibitors) for at least 5 half lives prior to first dose of study drug. Subjects may qualify if such
medication(s) can be safely replaced with alternate medications with less risk of drug-drug interaction.
14. Subjects with active COVID-19 infection.
15. Symptomatic and/or neurologically unstable CNS metastases, or who require an increase in steroid dose to control CNS disease. Subjects who have been receiving a stable steroid dose for at least 2 weeks prior to C1D1 may be allowed. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Study Endpoints (Phase 2):
Primary Endpoint
Objective response rate (ORR; defined as complete response [CR] + partial response [PR]) per independent review committee (IRC)
(BIRC) based on RECIST v1.1 criteria, RANO criteria for CNS tumors, or other relevant criteria per tumor type. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Timepoints are described within the text in section E.5.1 |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
- Median duration of response (DOR) per IRC.
- ORR per investigator assessment based on RECIST v1.1 criteria, RANO criteria for CNS tumors, or other relevant criteria per tumor type.
- Median DOR per investigator assessment.
- Antitumor activity by clinical benefit rate (CR + PR + SD ≥ 4 cycles) based on RECIST v1.1 criteria, RANO criteria for CNS tumors, or other
relevant criteria per tumor type.
- Median time to progression (TTP).
- Progression-free survival (PFS) and overall survival (OS) at 6, 12 18, and 24 months.
Safety and PK Assessments:
- Incidence of SAEs and AEs by relationship and severity grade, and incidence of SAEs/AEs leading to dose reduction, interruption or
discontinuation of study treatment.
-Trough PK assessments (sparse sampling) will be analyzed for Cmax, Cmin, AUC0-t, and other secondary PK parameters of APL-101 and APL-101 metabolites (if applicable)
- PK parameters will be assessed in a subset of subjects (those with CNS tumors receiving 300 mg BID) who volunteer to participate: Cmax, Cmin, AUC0-t, and other secondary PK parameters of APL-101 and APL-101 metabolites (if applicable).
Exploratory Assessments:
- Status of MET genetic alterations including MET amplification, Exon 14 skipping mutations, fusions, and other oncogenic mutations.
- MET protein expression by IHC.
- Other potential biomarkers of APL-101 activity as they become known.
- Tumor histology
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints are described within the text in section E.5.2 |
|
| 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 | No |
| 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 | Yes |
| 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 | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase 1/2 study with Phase 1 clinical experience |
|
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 47 |
| 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 |
| Russian Federation |
| United Kingdom |
| United States |
| Finland |
| France |
| Hungary |
| Italy |
| 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
|
| 6-months post last subject treatment |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 18 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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