To investigate how safe the new medicine pralsetinib is when it is administered to patients with non-resectable advanced solid tumor cancers including non-small cell lung cancer (NSCLC) and Thyroid cancers.
ID
Source
Brief title
Condition
- Other condition
- Respiratory and mediastinal neoplasms benign (excl mesotheliomas)
Synonym
Health condition
Thyroid Cancer, Non-Small Cell Lung Cancer (NSCLC) and Other Advanced Solid Tumors
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase 2, Dose Expansion Objectives
Primary Objectives
• To determine the overall response rate (ORR) by Response Evaluation Criteria
in Solid Tumors (RECIST) v1.1 (or Response Assessment in Neuro-Oncology [RANO],
if appropriate for tumor type) according to patients* disease type, and/or
RET-altered status if applicable, and/or prior treatment status if appropriate.
• To further define the safety and tolerability of pralsetinib
Secondary outcome
Secondary Objectives
• To assess additional measures of clinical benefit including DOR, CBR, DCR,
PFS, and overall survival (OS) in all patients according to patients* disease
type, and/or RET-altered status if applicable, and/or prior treatment status if
appropriate.
• To assess baseline RET gene status in plasma and/or tumor tissue and
correlate with measures of antineoplastic activity including, but not limited
to ORR, CBR, DOR, and DCR.
• To characterize the pharmacokinetic (PK) profile of pralsetinib and correlate
drug exposure with safety assessments, including changes in ECG intervals, and
efficacy.
• To characterize the pharmacodynamics of pralsetinib, including, but not
limited to, changes in blood calcitonin and carcinoembryonic antigen (CEA) in
MTC patients only.
• To assess brain activity in patients with NSCLC.
Exploratory Objectives
• To identify potential new blood and tumor tissue biomarkers (eg, DNA, RNA,
and/or protein markers) of pharmacodynamic activity, antineoplastic activity,
and/or toxicity.
• To assess changes in quality of life (QoL) questionnaire
• To explore disease-related symptoms, as measured by bowel movement history
(MTC patients only).
• To explore clinical benefit including ORR, CBR, DCR, PFS for patients
previously treated with a selective RET tyrosine kinase inhibitor.
• To assess brain activity in patients with tumor types other than NSCLC.
Background summary
Pralsetinib was designed to treat patients with tumors that have changes in the
RET (Rearranged during Transfection) gene that may make the tumors grow.
Changes in RET are found commonly in Thyroid cancer (medullary thyroid cancer -
MTC) and less commonly in other cancers such as NSCLC.
In Phase 2, all patients, except those with MTC, are required to have lab
results from previous testing of their tumor, indicating a change in the RET
gene before enrollment. All Phase 2 patients, including MTC, must also have
tumor tissue from a previous biopsy or from a new biopsy available for testing
that can be submitted for confirmatory testing and additional research tests.
Study objective
To investigate how safe the new medicine pralsetinib is when it is administered
to patients with non-resectable advanced solid tumor cancers including
non-small cell lung cancer (NSCLC) and Thyroid cancers.
Study design
This is a Phase 1/2, open-label, first-in-human (FIH) study designed to
evaluate the safety, tolerability, PK, pharmacodynamics, and preliminary
antineoplastic activity of pralsetinib, a potent and selective RET inhibitor,
administered orally in patients with medullary thyroid cancer, RET-altered
NSCLC and other RET-altered solid tumors.
The study consists of 2 parts, a dose-escalation part (Phase 1) and an
expansion part (Phase 2). The Netherlands will only take part in Phase 2 of the
study. The study will enroll patients with advanced non-resectable NSCLC,
advanced non-resectable thyroid cancer and other advanced non-resectable solid
tumors that have progressed following standard systemic therapy, have not
adequately responded to standard systemic therapy, or the patients must be
intolerant to or the Investigator has determined that treatment with standard
therapy is not appropriate, or there must be no accepted standard therapy for
their disease.
In Phase 2, patients will enroll into 1 of 7 groups based on their tumor type
and prior therapy status (if applicable), must have at least 1 target lesion
evaluable by RECIST v1.1 (or RANO, if appropriate):
• Group 1: NSCLC with a RET fusion previously treated with a platinum-based
chemotherapy (N ~80).
• Group 2: NSCLC with a RET fusion not previously treated with a platinum-based
chemotherapy including those who have not had any systemic therapy. Prior
platinum chemotherapy in the neoadjuvant and adjuvant setting is permitted if
the last dose of platinum was 4 months or more before the first dose of study
drug (N~200).
• Group 3: MTC previously treated with cabozantinib and/or vandetanib (N ~65).
• Group 4: MTC not previously treated with cabozantinib and/or vandetanib (N
~40)
• Group 5: Other solid tumors with a RET fusion not eligible for any of the
other groups (N ~100). Patients should have previously received SOC appropriate
for their tumor type, unless there is no accepted standard therapy for the
tumor type or the Investigator has determined that treatment with standard
therapy is not appropriate. As the intent of this cohort is to enroll a variety
of RET-fusion tumor types, Blueprint will notify sites if/when sufficient data
are available and accrual should cease for a particular tumor type.
• Group 6: Any Solid tumors with a RET alteration (fusion or mutation)
previously treated with a selective RET tyrosine kinase inhibitor (TKI)
• Group 7: Other Solid tumors with a RET mutation previously treated with SOC
appropriate for the tumor type (N ~20).
Determination of RET status as required for enrollment of all patients except
those with MTC, is based on local assessment, or central assessment if local
testing is not available. All patients enrolled in Phase 2 (all 7 groups) must
submit tumor tissue (archived or new) for retrospective assessment of RET
status and other pathway biomarkers. Patients enrolled into Group 6 (previously
treated with a selective RET-inhibitor) are required to have a new tumor biopsy
prior to enrollment.
All study visits are intended to be conducted on an outpatient basis, but may
be conducted on an inpatient basis, as needed. After provision of written
informed consent (within 8 weeks before study drug administration), patients
will be evaluated for study eligibility during the Screening period within 28
days before study drug administration on Cycle 1, Day 1 (C1D1).
On C1D1, eligible patients will present to the study center approximately 2
hours before the first dose of study drug and will remain at the study center
for at least 8 hours for serial PK sampling, pharmacodynamic sample collection,
vital signs measurement, electrocardiogram (ECG) monitoring, safety laboratory
tests, and safety monitoring. In Phase 2, patients will complete a QoL
assessments (EORTC QLQ-C30). Additionally, in Phase 2 only, continuous ECG
Holter monitoring will be performed approximately 1 hour before dosing until
after collection of the 8-hour PK sample for approximately 20 evaluable
patients at select study centers.
A treatment cycle is 28 days in duration. Initially, patients returned to the
study center on C1D2 for PK sampling (24 hours after the C1D1 dose), C1D8 and
C1D22 for safety monitoring, and on C1D15 and C1D16 for serial PK sampling and
safety monitoring (including continuous Holter monitoring for 20 patients in
Phase 2 at select study centers). Patients will also attend study center visits
on C2D1 and C2D15, on Day 1 of C3 through C13, C15, C17, C21 and every 4 cycles
thereafter for additional safety monitoring; PK and pharmacodynamic sampling;
and disease response assessment by computed tomography (CT) or magnetic
resonance imaging (MRI). In Phase 2 only, the European Organization for
Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC
QLQ-C30) will be administered on D1 of every cycle through C12. A tumor biopsy
will be performed within 2 weeks (±) of C2D1 (Phase 1 only) and upon disease
progression (both Parts), if the patient consents and the procedure is deemed
to be safe and medically feasible by the Investigator.
All patients will attend an End-of-treatment (EOT) visit approximately 14 days
(±7 days) after the last dose of study drug. A Follow-up telephone contact for
resolution of any residual adverse event (AE) will be made on Day 30 (+7 days)
after the last dose of study drug, or at the time the patient initiates another
antineoplastic therapy. All patients will be contacted every 3-4 months for PFS
and every 3 months for overall survival.
Intervention
In Phase 2, all patients will receive the same dose of pralsetinib, being 400
mg once daily in 28-day cycles.
The dose should be taken in the morning and should be taken at approximately
the same time each day. pralsetinib doses should be taken with a full glass of
water on an empty stomach. Subject should not eat anything 2 hours before and
until 1 hour after take the study drug.
Study burden and risks
Targeting oncogenic kinase mutants with selective inhibitors can provide
dramatic therapeutic benefit in advanced solid tumours as observed with EGFR,
ALK, and ROS1. However, there are no highly selective therapeutics currently
available for targeting RET-altered cancers and limited anti-tumour activity as
been demonstrated with multikinase inhibitors (MKIs). Additionally, MKIs are
associated with significant toxicity that limit dose intensity and may prevent
adequate suppression of RET-driven tumours. Therefore, RET-altered cancers
remain a significant medical need.
Given the strong genetic and preclinical evidence tht activated RET is an
oncogenic disease driver, the lack of selective RET inhibitors available, and
the poor prognosis of many patients with RET-driven tumours, the use of a
selective, targeted agent against this tumour alteration may be beneficial.
BLU-667 potently and selectively targets RET and RET-activated mutants such as
M918T and V804L/M, shows potent anti-tumour activity in RET-driven tumour
models, and demonstrates tolerability at pharmacologically active doses in
preclinical toxicology species. Results of preclinical pharmacology studies and
GLP toxicology studies with BLU-667 suggest that a manageable safety and
tolerability profile can be achieved in humans. Currently, patients with
advanced, RET-altered cancer have limited therapeutic options and poor
prognosis. BLU-667 may provide the potential for significant therapeutic
benefit in patients with RET-altered cancers as well as an acceptable risk
profile. Therefore, further development of pralsetinib is warranted in a
well-controlled, clinical trial setting.
(for the most updated data please refer to the Protocol summary and protocol
section 1.5).
Grenzacherstrasse 124 -
Basel 4070
CH
Grenzacherstrasse 124 -
Basel 4070
CH
Listed location countries
Age
Inclusion criteria
1. Patient is >= 18 years of age.
2. Diagnosis during dose escalation (Phase 1) - Pathologically
documented, definitively diagnosed non-resectable advanced solid
tumor.
• All patients treated at doses > 120 mg per day must have MTC, or a
RET-altered solid tumor per local assessment of tumor tissue and/or
blood.
• Phase 1 enrichment patients must have MTC or a RET-altered solid
tumor per local assessment of tumor tissue and/or blood.
3. Diagnosis during dose expansion (Phase 2) - All patients (with the
exception of patients with MTC enrolled in Groups 3 and 4) must have an
oncogenic RET fusion or
mutation (excluding synonymous, frameshift, and nonsense mutations)
solid tumor, as determined by local testing of tumor or circulating tumor
nucleic acid in blood; as detailed below.
• Group 1 - patients must have pathologically documented, definitively
diagnosed locally advanced or metastatic NSCLC with a RET fusion
previously treated with a platinum-based chemotherapy.
• Group 2 - patients must have pathologically documented, definitively
diagnosed locally advanced or metastatic NSCLC with a RET fusion not
previously treated with a platinum-based chemotherapy, including those
who have not had any systemic therapy. Prior platinum chemotherapy in
the neoadjuvant and adjuvant setting is permitted if the last dose of
platinum was 4 months or more before the first dose of study drug.
• Group 3 - patients must have pathologically documented, definitively
diagnosed advanced MTC that has progressed within 14 months prior to
the Screening Visit and was previously treated with cabozantinib and/or
vandetanib.
• Group 4 - patients must have pathologically documented, definitively
diagnosed advanced MTC that has progressed within 14 months prior to
the Screening Visit and was not previously treated with cabozantinib or
vandetanib.
• Group 5 - patients must have a pathologically documented, definitively
diagnosed advanced solid tumor with an oncogenic RET fusion, have previously
received SOC appropriate for their tumor type (unless there is no accepted
standard therapy for the tumor type or the investigator has determined that
treatment with standard therapy is not appropriate), and must not eligible for
any of the other groups.
• Group 6 - patients must have a pathologically documented, definitively
diagnosed advanced solid tumor with an oncogenic RET fusion or
mutation, previously treated with a selective TKI that inhibits RET, such
as LOXO-292.
• Group 7: patients must have a pathologically documented, definitively
diagnosed advanced solid tumor with an oncogenic RET mutation
previously treated with SOC appropriate for the tumor type and not
eligible for any of the other groups.
4. Patients must have non-resectable disease. Prior to protocol amendment 9,
patients
must have progressed following standard therapy or have not
adequately responded to standard therapy, or the patient must be
intolerant to, or the Investigator has determined that treatment with
standard therapy is not appropriate, or there must be no accepted
standard therapy for their disease.
5. Dose expansion (Phase 2) patients in all groups (except group 7) must
have measurable disease per RECIST v1.1 (or RANO, if appropriate for
tumor type).
6. Patient agrees to provide tumor tissue (archived, if available or a fresh
biopsy) for RET status confirmation and is willing to consider an
on-treatment tumor biopsy, if considered safe and medically feasible by
the treating Investigator. For Phase 2, Group 6, patients are required to
undergo a pretreatment biopsy to define baseline RET status in tumor
tissue.
7. Patient has Eastern Cooperative Oncology Group (ECOG) performance
status (PS) of 0-1.
8. Patient or legal guardian provides informed consent to participate in
the study.
Exclusion criteria
1. Patient's cancer has a known primary driver alteration other than RET.
Investigators should discuss enrollment with Sponsor regarding comutations
2. Patient has any of the following within 14 d prior to the first dose of
IMP:
a. Platelet count < 75 × 109/L
b. Absolute neutrophil count < 1.0 × 109/L
c. Hemoglobin < 9.0 g/dL red blood cell transfusion and erythropoietin
may be used to reach at least 9.0 g/dL, but must have been
administered at least 2 weeks prior to 1st IMP dose
d. AST or ALT > 3 × ULN if no hepatic metastases are present; > 5 × ULN
if hepatic metastases are present
e. Total bilirubin > 1.5 × ULN; > 3 × ULN with direct bilirubin > 1.5 ×
ULN in presence of Gilbert's disease
f. Estimated (Cockroft-Gault formula) or measured creatinine clearance
< 40 mL/min
g. Total serum phosphorous > 5.5 mg/dL
3. Patient has a QTcF > 470 msec. Patient has a history of prolonged QT
syndrome or Torsades de pointes. Patient has a familial history of
prolonged QT syndrome
4. Patient has 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
bradyarrhythmias that may cause QT prolongation
5. Patient has CNS metastases or a primary CNS tumor 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
6. Presence of clinically symptomatic interstitial lung disease or
interstitial pneumonitis, including radiation pneumonitis
7. Patient received the following anti-cancer therapy:
a. Any systemic anticancer therapy (except for immunotherapy or other
antibody therapies) and all forms of radiotherapy within 14 d or 5 halflives
prior to first IMP dose. IMP may be started within these washout
periods if considered by the Investigator to be safe and within the best
interest of the patient prior Sponsor approval
b. Any immunotherapy or other antibody therapy within 28 d prior to the
1st dose of IMP (immune related toxicities must have resolved to <
Grade 2 prior to starting IMP)
8. Dose expansion patients in Groups 1-5 and 7 (Phase 2): patient has
previously received treatment with a selective RET inhibitor such as
selpercatinib
9. Patient received neutrophil growth factor support within 14 d of 1st
IMP dose
10. Patient requires treatment with a prohibited medication or herbal remedy
that cannot be discontinued at least 2 weeks before start of IMP
administration. IMP may be started within 14 d or 5 half-lives of prior
therapy if considered by the Investigator to be safe and within the best
interest of the patient, with prior Sponsor approval
11. Patient has had a major surgical procedure within 14 d of the first
IMP dose
12. Patient has a history of another primary malignancy that has been
diagnosed or required therapy (except maintenance anti-hormonal
therapy) within the past year. The following prior malignancies are not
Not exclusionary are: completely resected basal cell and squamous cell
skin cancer, curatively treated localized prostate cancer, curatively
treated localized thyroid cancer, and completely resected carcinoma in
situ of any site
13. Patient is unwilling or unable to comply with scheduled visits, drug
administration plan, laboratory tests, or other study procedures and
study restrictions
14. Women who are unwilling, if not postmenopausal or surgically
sterile, to abstain from sexual intercourse or employ highly effective
contraception during IMP administration period and for at least 14 days
after the last IMP dose. Men who are unwilling, if not surgically sterile,
to abstain from sexual intercourse or employ highly effective
contraception during the IMP administration period and for at least 7
days after the last IMP dose
15. Pregnant females, as documented by a serum β-hCG pregnancy test
consistent with pregnancy, obtained within 7 days prior to the first dose
of study drug. Females with β-hCG values that are within the range for
pregnancy but are not pregnant (false-positives) may be enrolled with
written consent of the Sponsor, after pregnancy has been ruled out.
Females of non-childbearing potential (postmenopausal for more than 1
year; bilateral tubal ligation; bilateral oophorectomy; hysterectomy) do
not require a serum β-hCG test
16. If female, patient is breastfeeding
17. Patient has prior or ongoing clinically significant illness, medical
condition, surgical history, physical finding, or laboratory abnormality
that, in the Investigator's or Sponsor's opinion, could affect the safety of
the patient;
alter the absorption, distribution, metabolism, or excretion of the study
drug; or impair the assessment of study results
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-004390-41-NL |
| ClinicalTrials.gov | NCT03037385 |
| CCMO | NL67119.042.18 |