Primary* To compare TFFS of patients with progressive, advanced, kinase inhibitor naïve, RET-mutant MTC treated with LOXO-292 versus cabozantinib or vandetanib.Secondary* To compare other efficacy outcomes, based on RECIST 1.1 criteria, observed in…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Oncology - Thyroid
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* TFFS by BICR
Secondary outcome
* PFS by BICR
* TFFS by investigator
* TFFS by investigator
* ORR by investigator and BICR
* DoR by investigator and BICR
* OS
* PFS2 by investigator
* Safety per CTCAE v5.0 (including but not limited to): incidence and severity
of TEAEs, SAEs, deaths, and clinical laboratory abnormalities.
* FACT-GP5
* PRO CTCAE
Background summary
Medullary thyroid cancer (MTC) accounts for 1% to 2% of thyroid cancers in the
United States (SEER 2018). The majority of MTCs are sporadic, with
approximately 10% hereditary due to a germline activating mutation in the RET
gene. Most sporadic MTCs harbor activating RET mutations as well. The clinical
course of MTC is highly heterogeneous, varying from indolent tumors that remain
unchanged for many years to aggressive cancers associated with high mortality.
Although surgery can be curative for the approximately 85% of patients who
present with localized disease, approximately 50% develop recurrent disease.
Metastatic MTC is incurable. Treatment with the multikinase inhibitors (MKIs)
cabozantinib or vandetanib is the standard treatment for patients with
symptomatic and/or progressive metastatic MTC. However, the efficacy of these
MKIs is ultimately limited by incomplete inhibition of RET in tumors in
patients, significant toxicity from stronger inhibition of other targets and
poor pharmacokinetics (PK). As a result, most patients treated with these
agents experience significant toxicities requiring dose interruptions,
reductions (35% to 79%), and/or treatment cessation (12% to 16%) (Wells et al.
2012, Elisei et al. 2013). LOXO-292 is a highly potent and specific small
molecule inhibitor of the RET kinase, with minimal inhibition of other kinase
and non-kinase targets. A Phase 1/2 study (LIBRETTO-001) was designed to assess
the safety, PK and anti-tumor activity of LOXO-292 in patients with RET-altered
solid tumors. The Phase 1 portion of the study has been completed and the Phase
2 portion is ongoing. Initial data from Phase 1 was recently presented (Drilon
et al. 2018; Oxnard et al. 2018; Wirth et al. 2018). As of 02 April 2018, 82
patients were treated at 8 dose levels (20 mg QD to 240 mg BID).
Treatment-emergent adverse events (TEAEs) were monitorable and reversible. A
dose of 160 mg BID has been selected for Phase 2. The investigator-assessed
overall response rate (ORR) and confirmed ORR (cORR) by Response Evaluation
Criteria in Solid Tumors (RECIST) 1.1 in patients with RET mutant MTC were 59%
(n = 17/29) and 56% (n = 15/27, respectively, with 94% (n = 16/17) of responses
ongoing with a median follow up of 7.6 months (8.4 months for responders).
Given its manageable toxicity profile and evidence of durable antitumor
activity in patients with advanced RET mutant MTC, LOXO-292 may be of benefit
in delaying treatment failure and disease progression and improving survival in
patients with progressive, advanced MTC who have not previously received
cabozantinib or vandetanib.
Study objective
Primary
* To compare TFFS of patients with progressive, advanced, kinase inhibitor
naïve, RET-mutant MTC treated with LOXO-292 versus cabozantinib or vandetanib.
Secondary
* To compare other efficacy outcomes, based on RECIST 1.1 criteria, observed in
patients with progressive, advanced, kinase inhibitor naïve,
RET-mutant MTC treated with LOXO-292 versus cabozantinib or vandetanib.
* To evaluate the safety and tolerability of LOXO-292 compared to cabozantinib
or vandetanib.
* To compare the tolerability of LOXO-292 versus cabozantinib or vandetanib
* To assess/evaluate performance of local RET laboratory tests compared to a
single, central test.
* To assess the PK of selpercatinib in the patient population.
Study design
This is a global, multicenter, randomized (2:1), open-label, Phase 3 study
comparing LOXO-292 (treatment Arm A) to physicians choice of cabozantinib or
vandetanib (treatment Arm B) in patients with progressive, advanced, kinase
inhibitor naïve, RET-mutant MTC.
Patients will be stratified based on:
* RET mutation: M918T vs. other
* Geographic region: North America vs. Europe vs. Asia
* Intended treatment if randomized to control arm: cabozantinib vs. vandetanib
Patients with histologically confirmed, unresectable, locally advanced, or
metastatic MTC who have not received previous treatment with a kinase inhibitor
are eligible. Patients are required to have radiologic progressive disease per
RECIST 1.1 at screening compared with an image obtained within the prior 14
months and to have a documented RET mutation in tumor or germline DNA. Both
radiographic progression and RET mutation must be confirmed by the sponsor
prior to patient randomization. Patients will be randomized in a 2:1 ratio to
receive LOXO-292 (treatment Arm A) or physicians choice of cabozantinib
(treatment Arm B1) or vandetanib (treatment Arm B2). Patients assigned to the
control arm cannot switch from cabozantinib to vandetanib or from vandetanib to
cabozantinib during the study. Treatment will continue until disease
progression, unacceptable toxicity, or death. Patients randomized to Arm B who
discontinue treatment and who have radiographic disease progression that is
confirmed by blinded independent central review (BICR) may be eligible for
crossover to LOXO-292 if they meet the eligibility criteria for crossover (see
Section 5.2.1).
Intervention
Arm A: Intervention LOXO-292, twice daily
Arm B1: Intervention Cabozantinib, once daily
Arm B2: Intervention Vandetanib, once daily
Cycle length is 28 days for all treatment arms.
Study burden and risks
During the study, you will visit the hospital approximately 4 times per month,
the frequency of study visits may be higher than visits required as routine
practice by your doctor for looking after your illness, however these are
required for study participation. A visit will take approximately 1 hour during
the treatment period. The follow-up visits will take 30 minutes to 1 hour.
Venapunction : Yes
Biopsy: Possible
For more information see section E6 and Section J in this form, or the
protocol.
Island House, Eastgate Business Park, Little Island na
Cork Co.
NL
Island House, Eastgate Business Park, Little Island na
Cork Co.
NL
Listed location countries
Age
Inclusion criteria
1. Are of an acceptable age to provide informed consent according to local
regulations and
are at least 18 years of age (patients as young as 12 years of age will be
allowed if
permitted by local regulatory authorities and institutional review boards).
2. Histologically confirmed, unresectable, locally advanced and/or metastatic
MTC and no
prior history of treatment with kinase inhibitors for advanced/metastatic
disease. Prior
systemic or radiation therapy in the adjuvant setting may be allowed with
discussion and
approval by the Lilly CRS/CRP.
3. Radiographic progressive, measurable disease per RECIST 1.1 (Eisenhauer et
al. 2009) at
screening compared with a previous image taken within the prior 14 months as
assessed
by the BICR.
4. A RET gene alteration identified in a tumor, germline DNA or blood sample,
as defined
in Appendix 6 of the protocol. The RET alteration result should be generated
from a laboratory with
CLIA, ISO/EIC, CAP, or other similar certification. Lilly should be contacted
to discuss
test results from labs where such certification is not clearly demonstrated to
determine
eligibility. In all cases, a redacted Molecular Pathology Report or other
report(s)
describing tumor and/or germline RET (and other) alteration analysis should be
submitted to Lilly or designee during/prior to eligibility.
a. Mandatory provision of an unstained, archived tumor tissue sample in a
quantity
sufficient to allow for retrospective central analysis of RET mutation status
(for
confirmation). Please refer to Section 8.8.1 for details.
b. Participants must have adequate unstained, archived tumor tissue sample, as
defined in Section 8.8.1, for retrospective central confirmation of the RET
result.
5. Eastern Cooperative Oncology Group (ECOG) performance status score (Oken et
al.
1982) of 0 to 2.
6. Ability to swallow capsules and comply with treatment, laboratory
monitoring, and
required clinic visits for the duration of study participation
7. Patients must have discontinued from previous treatments as shown in the
protocol and fully
recovered. Consult with the Lilly CRS/CRP for the appropriate length of time
prior to
the first dose of study treatment on additional therapies not mentioned.
8. Have adequate organ function, as defined in the protocol.
9. Patients must have normal serum potassium, calcium, and magnesium levels
(may be
receiving supplements).
10. Men with partners of childbearing potential or women of childbearing
potential must
agree to use a highly effective contraceptive method (for example, intrauterine
device
[IUD], birth control pill, or barrier method) during treatment with study drug
and for
6 months following the last dose of study drug. If a condom is used as a barrier
contraceptive, a spermicidal agent should be added as double-barrier
protection. See
Appendix 3 of the protocol.
Note: Unless not allowed by local regulations, women of childbearing potential
who are
abstinent (if this is complete abstinence, as their preferred and usual
lifestyle) or in a
same-sex relationship (as part of their preferred and usual lifestyle) must
agree to either
remain abstinent or stay in a same-sex relationship without sexual
relationships with
males unless they agree to use contraceptive method known to be highly
effective.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation
methods),
declaration of abstinence just for the duration of a trial, and withdrawal are
not
acceptable methods of contraception.
11. Women of childbearing potential must have a negative pregnancy test (serum
or urine,
consistent with local regulations) documented within 24 hours prior to
treatment with
study drug.
12. Capable of giving signed informed assent/consent as described in Appendix 1
of the protocol, which includes compliance with the requirements and
restrictions listed in the informed consent
form (ICF) and in the protocol.
Exclusion criteria
13. An additional validated oncogenic driver in MTC if known that could cause
resistance to
LOXO-292 treatment. Examples include, but are not limited to RAS gene mutations
and
ALK gene fusions.
14. Symptomatic CNS metastases, leptomeningeal carcinomatosis, or untreated
spinal cord
compression. Patients are eligible if neurologically stable and without
increase in steroid
dose for 14 days prior to the first dose of study treatment and no CNS surgery
or
radiation has been performed for 28 days, 14 days if stereotactic radiosurgery
(SRS).
15. Clinically significant active cardiovascular disease or history of
myocardial infarction
within 6 months prior to planned start of study treatment or prolongation of
the QT
interval corrected for heart rate using Fridericia*s formula (QTcF) >470 msec
on more
than one ECG during Screening. Correction of suspected drug-induced QTcF
prolongation may be attempted at the investigator*s discretion if clinically
safe to do so.
Patients who are intended to receive vandetanib if randomized to the control arm
ineligible if QTcF is >450msec.
a. Note: Patients with implanted pacemakers may enter study without
meeting QTc criteria due to nonevaluable measurement.
16. Active uncontrolled systemic bacterial, viral, or fungal infection or
serious ongoing
intercurrent illness, such as hypertension or diabetes, despite optimal
treatment, a clinical
diagnosis or symptoms of interstitial lung disease, or other serious medical
conditions which in the medical judgment of the investigator would prevent the
patient from safely
participating (screening for chronic conditions is not required).
17. Clinically significant active malabsorption syndrome or other condition
likely to affect
gastrointestinal absorption of the study drug.
18. Uncontrolled symptomatic hyperthyroidism or hypothyroidism
19. Uncontrolled symptomatic hypercalcemia or hypocalcemia
20. Active hemorrhage or at significant risk for hemorrhage.
21. Other malignancy unless nonmelanoma skin cancer, carcinoma in situ of the
cervix or
malignancy diagnosed >=2 years previously and not currently active. Patients
receiving
adjuvant hormone therapy for breast or prostate cancer with no evidence of
disease are eligible. Participants with MEN2-associated pheochromocytoma are
eligible if the pheochromocytoma is, in the opinion of the investigator,
documented to be stable or has been resected (and patient has fully recovered
from surgery).
22. Prior systemic treatment with kinase inhibitor(s)
23. Require concomitant use of strong CYP3A4 inhibitors or inducers (see
Appendix 7 of the protocol)
24. Require treatment with proton pump inhibitors (PPIs)
25. Are taking a concomitant medication that is known to cause QTc prolongation
(for
examples, see Appendix 7 of the protocol)
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 | EUCTR2019-001978-28-NL |
| CCMO | NL71643.031.19 |