The primary objective is to assess treatment with rovalpituzumab tesirine improves overall survival rate (OS) compared to topotecan in subjects with DLL3high SCLC who have first disease progression during or following front-line platinum based…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Overall survival (OS)
Timepoints of evaluation of this endpoint:
- Overall Survival is defined as the time from the date of randomization to the
date of death from any cause (i.e., date of subject*s death - date of
randomization +1)
Secondary outcome
- Progression-free survival (PFS) based on the CRAC per RECIST v1.1,
- Duration of objective response (DOR) based on the CRAC per RECIST v1.1,
- Patient reported outcomes (PROs)
Timepoint(s) of evaluation of this endpoint
- PFS is based on independent review of tumor assessment, defined as the time
from randomization to documented CRAC-assessed disease progression or death
from any cause (whichever occurs earlier).
- DOR is defined as the time between the date of the first response (CR or PR,
whichever is recorded first) to the date of the first documented tumor
progression (per RECIST 1.1) or death due to any cause, whichever comes first.
Background summary
Small cell lung cancer (SCLC) is an important unmet medical need, representing
15 - 20% of the 220.000 annual new cases of lung cancer in the US. SCLC can be
staged using the Veterans Administration Lung Study Group (VA LG)
classification, which distinguishes between limited and extensive stage
disease, or the TNM-classification. Approximately two-third of newly diagnosed
subjects will have extensive stage SCLC.
Systemic chemotherapy (platinum salt in combination with etoposide or
irinotecan) remains the cornerstone of therapy for all stages of SCLC. For
subjects with limited stage disease, concurrent or sequential involved-field
thoracic radiotherapy is indicated. Response rates to initial therapy are high;
ranging from 70 - 90% for limited stage and 60 - 70% for extensive stage.
However, responses are typically not durable and recurrence rates are high in
the limited stage disease and nearly universal in the extensive stage disease,
leading to median survivals of 14 - 20 months and 9 - 11 months, respectively.
For subjects with relapsed/recurrent SCLC, options are limited. The
topoisomerase I inhibitor topotecan is currently the only agent with several
global regulatory approvals, but its activity is less than impressive and
associated toxicity is significant. Therefore, exploration of new therapies in
second line SCLC is warranted, with the goals of extending disease control and
improving overall survival.
The positive results of a phase 1 trial support the further clinical
development of Rova-T
Study objective
The primary objective is to assess treatment with rovalpituzumab tesirine
improves overall survival rate (OS) compared to topotecan in subjects with
DLL3high SCLC who have first disease progression during or following front-line
platinum based chemotherapy.
The secondary objectives are:
1. Assess if treatment with rovalpituzumab tesirine improves progression free
survival (PFS) compared to topotecan in subjects with advanced or metastatic
DLL3high SCLC who have first disease progression during or following front-line
platinum based chemotherapy,
2. Compare the duration of response of object response between two arms,
3. To assess the pharmacokinetics (PK) and immunogenicity of rovalpituzumab
tesirine,
4. Assess the effect on patient reported outcomes (i.e. health-related quality
of life and symptom assessment) due to treatment with rovalpituzumab tesirine
compared to topotecan in subjects with DLL3high SCLC who have first disease
progression during or following front-line platinum based chemotherapy.
5. To assess if the treatment with rovalpituzumab tesirine improves objective
response rate and clinical benefit rate compared to topotecan in subjects with
advanced advanced or metastatic DLL3high SCLC who have first disease
progression during or following front-line platinum based chemotherapy.
6. To compare the duration of objective response between two arms.
Study design
This is a phase 3 randomized, open-label, multicenter study comparing Rova-T
with topotecan in subjects with advanced or metastatic DLL3high SCLC who have
first disease progression during or following front-line platinum-based
chemotherapy. Subjects will be randomized in a 2:1 ratio to receive Rova-T or
topotecan. Subjects receiving Rova-T will also receive 8 mg orally of
dexamethasone twice daily on Day -1, Day 1 and Day 2 of each cycle in which
Rova-T is administered. Survival follow-up will continue until the endpoint of
death, the subject becomes lost to follow-up or withdraws consent or
termination of the study by AbbVie, whichever occurs first.
Randomization will be stratified by prior history of brain metastases (yes
versus no), prior PCI (yes vs. no) for subjects with no prior history of brain
metastases, sensitivity to first line platinum-based regimen and LDH (> ULN vs.
<= ULN) at screening. Approximately 411 subjects will be enrolled worldwide.
Intervention
Subjects in the Rova-T arm will receive Rova-T (IV) on Day 1 of each 42-day
cycle, and 8 mg orally of dexamethasone twice daily on Day -1, Day 1 and Day 2
of each cycle in which Rova-T is administered. The regimen of this arm will be
administered for 2 cycles unless earlier discontinuation is warranted, or up to
2 additional cycles for subjects who satisfy the criteria as specified in the
protocol. Subjects in this arm have clinic visits conducted for Screening, Days
1/22 of each cycle, End of Treatment (EoT) and every 6 weeks during the
post-treatment follow-up phase. Subjects will be advised to avoid unprotected
sun exposure due to Rova-T related skin photosensitivity.
Subjects in the topotecan arm will receive topotecan (IV) on Days 1 - 5 of each
21-Day cycle (topotecan may be administered at a lower dose if required by the
local label). All subjects in this arm will continue to receive topotecan until
disease progression, unless earlier discontinuation is warranted due to
unacceptable toxicity or any other reason. Subjects in this arm will have
clinic visits conducted for Screening, Days 1-5 of each cycle, EoT and every 6
weeks during the post-treatment follow-up phase.
For both arms, disease progression will be assessed every 6 weeks by a CT-scan.
An echocardiogram will be done on Day 1 of each cycle and the EoT visit to
assess pericardial effusion. Subjects will be asked to monitor their weight via
a daily fluid retention questionnaire.
An EoT visit will be conducted once disease progression is identified or when a
subject meets other criteria for study treatment discontinuation. The EoT visit
is the last visit during the treatment phase before a subject enters the post
treatment follow-up (PTFU) phase and/or Survival follow-up phase.
For all subjects without disease progression, PTFU visits will be conducted
every 6 weeks after the last dose of investigational product. After disease
progression or study discontinuation, the subject enters the survival follow-up
period. During this period, the subject will be contacted every 6 weeks for
subsequent anti-cancer therapies as well as survival status. These visits will
occur every 6 weeks (±1 week) until the endpoint of death, the subject becomes
lost to follow-up or withdraws consent, or termination of the study by AbbVie,
whichever occurs first.
Study burden and risks
The burden for the subjects consists of extra visits to the site, two ECGs, two
echocardiograms, additional blood draws on top of the standard lab draws, daily
weights, completion of QoL questionnaires and the fluid retention
questionnaire, 6-weekly CT-scans and four urinalyses. Subjects will remain in
the study until progression of disease is identified or when other
discontinuation criteria have been met. While the subject is still on the
study, no additional anti-cancer therapies may be started.
The most frequent treatment-emergent adverse events (TEAE) terms considered
related to Rova-T have included fatigue (35%), pleural effusion (28%) and
peripheral edema (26%), while the most frequent, related TEAE groups of Grade 3
or higher have included thrombocytopenia (10%), serosal effusions (13%), and
skin reactions (10%). In addition, preclinical toxicology studies conducted in
the rat and the cynomolgus monkey have identified bone marrow, lung, liver and
kidney as potential sources of clinical adverse events.
Wegalaan 9
Hoofddorp 2132JD
NL
Wegalaan 9
Hoofddorp 2132JD
NL
Listed location countries
Age
Inclusion criteria
1) Subjects must be an age of 18 years or older, providing written
informed consent
2) Histologically or cytologically confirmed advanced or metastatic SCLC
with documented first disease progression after or during front-line
platinum-based systemic regimen.
3) Tumor must have high DLL3 expression (DLL3high) defined as having
> 75% tumor cells staining positive according to the VENTANA DLL3
(SP347) IHC Assay. Archived or fresh tumor material can be used for the
DLL3 testing.
4) Eastern Cooperative Oncology Group (ECOG) performance status of 0
or 1.
5) Females of childbearing potential must have a negative serum
pregnancy test result at Screening, and a negative urine pregnancy test
at randomization. Females of non-childbearing potential (either
postmenopausal or permanently surgically sterile) at Screening do not
require pregnancy testing.
Exclusion criteria
1) Any significant medical condition that, in the opinion of the
investigator or Sponsor, may place the subject at undue risk from the
study, including but not necessarily limited to uncontrolled hypertension
and/or diabetes, clinically significant pulmonary disease or neurological
disorder (e.g., seizure disorder active within 6 months)
2) Documented history of a cerebral vascular event (stroke or transient
ischemic attack), unstable angina, myocardial infarction, or cardiac
symptoms consistent with New York Heart Association (NYHA) Class III
- IV within 6 months prior to their first dose of study drug.
3) Subject has known leptomeningeal metastases
4) Subject has Isolated CNS disease progression with no evidence of
progression outside of CNS
5) Subject has more than one prior systemic therapy regimen for SCLC
(prior systemic maintenance therapy following front-line platinum based
regimen, administered as part of clinical trial is allowed)
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 | EUCTR2016-003726-17-NL |
| ClinicalTrials.gov | NCT03061812 |
| CCMO | NL60441.042.17 |