| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| EGFR Mutant Non-Small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| EGFR Mutant Non-Small Cell Lung Cancer |
|
| 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 | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| 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 |
Phase 1:
- To determine the MTD and RP2D of BLU 945 as monotherapy and in combination with osimertinib.
- To determine the safety and tolerability of BLU 945 as monotherapy and in combination with osimertinib.
Phase 2:
- To assess anticancer activity of BLU 945 at the RP2D as monotherapy and in combination with osimertinib in patients with NSCLC harboring EGFR mutations. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1:
- To assess anticancer activity of BLU 945 as monotherapy and in combination with osimertinib
- To characterize the PK profile of BLU 945 and correlate drug exposure with safety assessments .
- Assess treatment-induced modulation of EGFR pathway biomarkers.
Phase 2:
- To assess additional measures of anticancer activity of BLU 945 at the RP2D as monotherapy and in combination with osimertinib in patients
with NSCLC harboring EGFR mutations.
- To determine the safety and tolerability of BLU 945 as monotherapy and in combination with osimertinib.
- To assess the effect of BLU 945 on cardiovascular intervals, including QT, and rhythm
- To characterize the PK profile of BLU 945 and correlate drug exposure with safety assessments, including changes in ECG intervals and antitumor activity. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- ≥18 years of age at the time of signing the informed consent.
- Pathologically confirmed, definitively diagnosed, metastatic NSCLC
harboring an activating EGFR mutation.
- Previously received at least 1 prior EGFR-targeted TKI with activity
against the T790M mutation, such as osimertinib.
a. Phase 1 Part 1B and Phase 2 Group 4: Patients must have experienced
progressive disease while on osimertinib, were able to tolerate prior
osimertinib 80 mg QD dose, and continuing on osimertinib is deemed to
be in the patient's best interests in the opinion of the Investigator.
Patients who have discontinued osimertinib may be eligible if no more than 6 weeks elapse between the discontinuation of prior osimertinib and resumption of osimertinib on study.
-Tumor mutation profile determined locally via a Sponsor-approved testing methodology, (NGS is preferred and will be required for Phase 2), using tumor tissue (ideally from a progressing lesion) and/or ctDNA in plasma. For Phase I, it is preferable that samples used for analysis be obtained during or after disease progression on the last EGFR-targeted TKI received. For Phase 2, pretreatment tumor sample must be obtained during or after disease progression on the last EGFR-targeted TKI received.
a. Dose Escalation (Phase 1 Parts 1A and 1B): At each dose level, slots may be reserved for patients with the mutations of interest.
b. BLU-945 Monotherapy Expansion (Phase 2 Group 1, Group 2, and Group 3): Patients must have NSCLC harboring EGFR T790M and C797S mutation (Group 1); EGFR T790M but not C797S (Group 2); or EGFR C797S but not T790M (Group 3).
c. BLU-945 with Osimertinib Expansion (Phase 2 Group 4): Slots may be reserved for patients with mutations of interest, but at least 12 slots will be allocated to patients with NSCLC harboring EGFR T790M and C797S mutation.
- Pretreatment tumor sample (either an archival sample or a sample obtained by pretreatment biopsy) submitted for central analysis. For Phase I, it is preferable that pretreatment tumor samples be obtained from a progressing lesion, during or after disease progression on the last EGFR-targeted TKI received. For Phase 2, pretreatment tumor sample must be obtained during or after disease progression on the last EGFRtargeted TKI received. Patients without appropriate archival tissue available, where biopsy is not considered safe and/or medically feasible, may be discussed with the study medical monitor and may be approved for enrollment on a case-by-case basis.
- Phase 2 Expansion Groups: Patient has at least 1 measurable target lesion evaluable by RECIST 1.1 as assessed by the investigator.
- Eastern Cooperative Oncology Group (ECOG) performance status is 0-1.
- Agrees to use contraception consistent with the protocol and local regulations. |
|
| E.4 | Principal exclusion criteria |
- Tumor harbors any additional known driver alterations (including but not limited to EGFR exon 20 insertion, or pathologic abnormalities of KRAS, BRAF V600E, NTRK1/2/3, HER2, ALK, ROS1, MET, or RET.
- NSCLC with mixed cell histology or a tumor with histologic transformation (NSCLC to SCLC, SCLC to NSCLC, or epithelial to mesenchymal transition).
- Received the following anticancer therapy:
a.EGFR-targeted TKI within 7 days prior to the first dose of study drug.
Note: patients in Phase 1 Part 1B and Phase 2 Group 4 do not require a wash-out period for osimertinib.
b.Any immunotherapy or other antibody therapy (including EGFR targeted antibodies or bi-specific antibodies) within 28 days prior to the first dose of study drug (immune-related toxicities must have resolved to < Grade 2 prior to starting BLU 945).
c.Any other systemic anticancer therapy within 14 days or 5 half-lives prior to the first dose of study drug, whichever is the shortest, but with a
minimum of 7 days in all circumstances. BLU 945 may be started within these washout periods if considered by the Investigator to be safe and
within the best interest of the patient, with prior Sponsor approval.
d.Radiotherapy to a large field or including a vital organ (including whole brain radiotherapy or stereotactic radiosurgery to brain) within 14 days
before the first dose of study drug. Participant received radiotherapy to a focal site of disease that did not include a vital organ (such as a limb)
within 7 days before the first dose of study drug.
- CNS metastases or spinal cord compression 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 treatment. Asymptomatic CNS and leptomeningeal disease is allowed and, when measurable, should be
captured as target lesions.
- Any of the following abnormalities on the most recent laboratory test prior to the first dose of study drug (ie, Cycle 1 Day 1[C1D1] or
screening):
a.Absolute neutrophil count (ANC) <1.0×10^9/L.
b.Platelet count <75×109/L.
c.Hemoglobin ≤8.0 g/dL (red blood cell transfusion and erythropoietin may be used to reach at least 8.0 g/dL, but must have been
administered at least 2 weeks prior to the first dose of study drug).
d.Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3× the upper limit of normal (ULN) if no hepatic metastases are
present; >5× ULN if hepatic metastases are present.
e.Total bilirubin >1.5× ULN; >3× ULN in presence of Gilbert's disease.
f.Estimated (Cockroft-Gault formula, Appendix 1) or measured creatinine clearance <40 mL/min.
g.International normalized ratio (INR) >2.3 or prothrombin time (PT) >6 seconds above control or a patient-specific INR or PT abnormality that
the treating investigator considers clinically relevant and/or increases the risk for hemorrhage in that individual patient.
- Known intracranial hemorrhage and/or bleeding diatheses.
- Clinically active ongoing interstitial lung disease (ILD) of any etiology, including drug-induced ILD, and radiation pneumonitis within 28 days
prior to initiation of study treatment. Patients with prior ILD associated with clinically resolved COVID 19 infection may be enrolled upon
discussion with, and approval by, the Medical Monitor.
- Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or that have
not resolved to baseline at the time of starting the study. Exceptions include alopecia and fatigue, and, upon discussion with and approval by
the Medical Monitor, other toxicities that are not thought to present a risk to
patient safety.
- Mean resting QT interval corrected using Fridericia's formula (QTcF) >450 msec, a history of prolonged QT syndrome or Torsades de pointes,
or a familial history of prolonged QT syndrome.
- Clinically significant, uncontrolled, cardiovascular disease including congestive heart failure Grade III or IV according to the New York Heart
Association classification; myocardial infarction or unstable angina within the previous 6 months, uncontrolled hypertension, or clinically
significant, uncontrolled arrhythmias, including bradyarrhythmia that may cause QT prolongation (eg, Type II second degree heart block or
third degree heart block)
Please, further information can be found in section 5.3 of the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1:
- MTD determination: DLT rate
- RP2D determination: DLT, PK, PD, and preliminary safety and anticancer activity data
-Overall safety profile of BLU-945, as assessed by the type, frequency, severity, timing, and relationship to study drug of treatment-emergent adverse events (TEAEs), and changes in vital signs, electrocardiograms and safety laboratory tests.
Phase 2:
- ORR, defined as the proportion of patients who experience a best response of confirmed CR or PR according to RECIST 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1:
- MTD determination: Up to 12 months
- RP2D determination: Up to 12 months
-Overall safety profile of BLU-945: Throughout Phase 1
Phase 2:
- ORR: Up to 30 months |
|
| E.5.2 | Secondary end point(s) |
Phase 1:
- ORR, defined as the proportion of patients who experience a best response of confirmed CR or PR according to RECIST 1.1
Phase 2:
- DCR, defined as the proportion of patients who experience a best response of CR, PR, or stable disease (SD) according to RECIST 1.1
- CBR, defined as the proportion of patients who experience a confirmed CR or PR, or SD with a duration of at least 16 weeks according to RECIST 1.1
- PFS, defined as the time from the first dose of BLU 945 until the date of first documented progressive disease or death due to any cause, whichever occurs first
- Overall survival (OS), defined as the time from the first dose of BLU 945 until the date of death due to any cause
- Time to intracranial progression and intracranial response rate in accordance with modified RECIST criteria
- Overall safety profile of BLU 945, as assessed by the type, frequency, severity, timing, and relationship to study drug of TEAEs, and changes in vital signs, electrocardiograms, and safety laboratory tests.
- ECG parameters extracted from continuous 12 lead Holter recordings for 25 patients in the expansion phase: The primary QTc parameter will be QTcF. Secondary parameters (other correction methods for QT, heart rate, PR, QRS, and T wave morphology) will also be evaluated.
- CNS-ORR, defined as the proportion of patients with measurable (target) intracranial metastases at baseline who experience a confirmed
intracranial CR or PR according to RECIST 1.1 principles
- CNS-DOR, defined as the time from first documented intracranial CR or PR to the date of first documented intracranial PD
- CNS progression rate, defined as the proportion of patients with CNS progression as a component of first disease progression on study.
- Correlations between PK parameters and safety findings of interest, including ECG intervals, will be performed
Phase 1 and Phase 2:
- DOR, defined as the time from first documented response of CR or PR to the date of first documented progressive disease or death due to any cause, whichever occurs first
- PK parameters of BLU-945
- Profile pharmacodynamic changes in expression levels of the EGFR pathway biomarkers dual specificity phosphatase (DUSP6) and sprouty RTK signaling antagonist 4 (SPRY4).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1:
- ORR: Up to 12 months
Phase 2:
-DCR and CBR: Up to 30 months
-PFS and OS: Up to 42 months
-Time to intracranial progression and intracranial response rate: Up to 42 months
-Overall safety profile: Up to 42 months
-ECG parameters: Up to 25 months
- CNS-ORR: Up to 42 months
- CNS-DOR: Up to 42 months
- CNS progression rate: Up to 42 months
Phase 1 and Phase 2:
-DOR: Up to 42 months
-PK parameters: Up to 42 months
-Profile pharmacodynamic changes in the EGFR pathway biomarker expression of DUSP6 and SPRY4: Up to 42 months
|
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Information not present in EudraCT |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| 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.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 |
| Canada |
| Japan |
| Korea, Republic of |
| Singapore |
| Taiwan |
| United States |
| France |
| Netherlands |
| Spain |
| Germany |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 6 |
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