Primary Objective• To compare the anti-tumor efficacy of oral single-agent rociletinib, as measured by investigator assessment of the progression-free survival (PFS), with that of single-agent cytotoxic chemotherapy in patients with EGFR mutated,…
ID
Source
Brief title
Condition
- Lower respiratory tract disorders (excl obstruction and infection)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
• PFS according to RECIST Version 1.1 as determined by investigator assessment
(invPFS)
Secondary outcome
Secondary Endpoints:
• ORR and DR according to RECIST Version 1.1 as determined by investigator
assessment
• OS
• Treatment-emergent adverse events (AEs), laboratory abnormalities, and
electrocardiogram (ECG) abnormalities
• Plasma PK parameters for rociletinib based on sparse sampling
Exploratory Endpoints
• DCR according to RECIST version 1.1 as determined by investigator
assessment
• Time-to-treatment failure
• OS, ORR, PFS, DR, and DCR in patients who cross over to receive rociletinib
and in patients who continue to receive rociletinib beyond progression
• Change from baseline in PROs using the European Organization for Research and
Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ C30), the
EORTC Quality of Life Questionnaire Lung Cancer module (EORTC QLQ LC13) and in
the EQ-5D
• Change from baseline in mutant EGFR levels in ctDNA obtained from plasma and
urine
• OS, ORR, PFS, DR, and DCR based on plasma and urine EGFR mutation test results
• Positive and negative percent agreement between blood, urine and tissue
results for T790M
• Identify biomarkers associated with response or resistance to rociletinib
Background summary
Rociletinib (CO 1686) is a novel, potent, small molecule irreversible TKI that
selectively targets mutant forms of the epidermal growth factor receptor (EGFR)
while sparing wild-type (WT) EGFR. Clovis Oncology, Inc. (Clovis) is developing
rociletinib as a therapeutic agent to be administered orally to patients with
mutant EGFR NSCLC.
Activating EGFR mutations are key drivers of NSCLC in 10% to 15% of patients of
European descent and approximately 30% of patients of East Asian descent.
Patients with the most common EGFR mutations, exon 21 L858R and deletions in
exon 19, typically have good responses to therapy with first generation EGFR
inhibitors such as erlotinib or gefitinib, and also with the second generation
inhibitor afatinib. Toxicity associated with erlotinib, gefitinib, and afatinib
includes skin rash and diarrhea related to inhibition of the WT EGFR in skin
and intestine, respectively.
Despite an impressive initial response to treatment, progression generally
occurs after 9-14 months of erlotinib, gefitinib, or afatinib therapy, driven
in approximately 60% of cases by a second site EGFR mutation in exon 20 called
T790M (the *gatekeeper* mutation) which mediates resistance to first and second
generation EGFR inhibitors. There are no approved therapies that target T790M
specifically, and standard of care remains cytotoxic chemotherapy. Yu et al
reported that T790M positive (T790M+) disease is fatal, with a median overall
survival (OS) of less than 2 years.
Nonclinical data demonstrate that rociletinib inhibits T790M as well as the
common activating mutations (L858R, del19) and has minimal inhibitory activity
towards WT EGFR at therapeutic doses. It is anticipated that rociletinib will
promote cell death in tumor cells with the T790M mutation, thus driving
objective tumor responses and providing therapeutic benefit in patients who
have acquired T790M mediated resistance to first generation EGFR inhibitors.
In the first in human study, CO 1686 008, in patients with advanced EGFR
mutation positive NSCLC and previous treatment with an EGFR inhibitor, no
maximum tolerated dose (MTD) was observed and 3 doses levels, 500 mg twice
daily (BID), 625 mg BID, and 750 mg BID, were selected for further clinical
evaluation of safety, tolerability and efficacy in the expansion cohorts.
Maturing data from this study suggest that patients treated with rociletinib at
500 mg BID and 625 mg BID experience responses that are comparable in
frequency, depth, and duration, with an overall acceptable safety profile for
this advanced cancer patient population. This current study will describe the
risk/benefit profile of the rociletinib 500 mg BID and 625 mg BID doses.
As expected, due to its selectivity for mutant EGFR, events typical of WT EGFR
inhibition (the combination of rash and chronic diarrhea) have not been
observed with rociletinib. Furthermore, heavily pretreated patients have
experienced durable Response Evaluation Criteria In Solid Tumors (RECIST)
responses. The majority of these responders had most recently been treated with
an EGFR TKI. Moreover, initial clinical data suggest that rociletinib may
provide clinical benefits to patients who test negative with respect to the
T790M mutation and the study has been designed to specifically investigate the
effectiveness of rociletinib in this group of patients.
The goals of the current study (Protocol CO 1686-020) are to compare the anti
tumor efficacy and safety of oral single-agent rociletinib with that of
single-agent cytotoxic chemotherapy in patients with EGFR mutated,
advanced/metastatic NSCLC after failure of at least 1 previous EGFR-directed
TKI and 1 line of platinum containing doublet chemotherapy. An additional goal
will be to determine the effectiveness of rociletinib in patients who test
negative with respect to the T790M mutation.
Rociletinib is being developed with a companion diagnostic (Qiagen, United
Kingdom) to identify patients whose tumors express activating EGFR mutations as
well as the T790M resistance mutation.
Study objective
Primary Objective
• To compare the anti-tumor efficacy of oral single-agent rociletinib, as
measured by investigator assessment of the progression-free survival (PFS),
with that of single-agent cytotoxic chemotherapy in patients with EGFR mutated,
advanced/metastatic NSCLC after failure of at least 1 previous EGFR-directed
TKI and at least 1 line of platinum-containing doublet chemotherapy
Secondary Objectives
• To compare secondary measures of clinical efficacy (duration of response
[DR], objective response rate [ORR], and OS) between patients randomized to
rociletinib or single-agent cytotoxic chemotherapy
• To compare the safety and tolerability of rociletinib with that of single
agent cytotoxic chemotherapy
• To determine pharmacokinetics (PK) of rociletinib using population PK (POPPK)
methods and explore correlations between PK, exposure, response, and/or safety
findings in patients randomized to rociletinib
Exploratory Objectives
• To evaluate clinical benefit of continued rociletinib treatment following
disease progression in patients randomized to the rociletinib arm
• To evaluate clinical benefit of rociletinib treatment following disease
progression in patients randomized to the comparator arm who cross over to
receive rociletinib
• To compare quality of life (QoL) by patient-reported outcomes (PRO) between
patients randomized to rociletinib or single-agent cytotoxic chemotherapy
• To evaluate concordance of mutant EGFR detection between tissue, urine, and
plasma and assess rociletinib mediated alterations in mutant EGFR levels over
time using circulating tumor deoxyribonucleic acid (ctDNA) obtained from
plasma; analyze clinical endpoints based on plasma and urine EGFR mutation test
results and compare findings from rociletinib treated patients with those
treated with single-agent cytotoxic chemotherapy
• To explore tissue, urine, and blood-based biomarkers that may be predictive
of response or primary resistance to rociletinib and investigate mechanisms of
acquired resistance in the tissue, urine, and blood of patients who experience
clinical progression during treatment with rociletinib and compare findings
from rociletinib treated patients with those treated with single agent
cytotoxic chemotherapy
Study design
This is a Phase 3, randomized, open-label, multicenter study evaluating the
safety and efficacy of oral rociletinib compared with that of single-agent
cytotoxic chemotherapy, in patients with previously treated mutant EGFR NSCLC.
Eligible patients are those with mutant EGFR NSCLC previously treated with at
least 1 EGFR inhibitor and at least 1 line of platinum containing chemotherapy
doublet for advanced/metastatic NSCLC.
After providing informed consent to participate and screening to confirm
eligibility, patients will be randomized 1:1:1 to receive rociletinib 500 mg
BID, rociletinib 625 mg BID, or single-agent cytotoxic chemotherapy
(investigator choice of pemetrexed, gemcitabine, docetaxel, or paclitaxel;
choice of chemotherapy agent must be specified before randomization).
Randomization will be stratified according to:
1. History of brain metastases versus no history of brain metastases,
2. Eastern Cooperative Oncology Group (ECOG) performance status 0 versus ECOG
performance status 1,
3. Territory of residence at time of randomization (East Asian versus non-East
Asian).
All patients will provide a tumor biopsy during screening for central
determination of T790M mutation status; tissue must be sent to the central
laboratory before randomization. Switching therapy after biopsy sampling is not
permitted as this may impact on the T790M mutation status. However, dose
reduction of the therapy adopted at that time is permitted.
The treatment cycle length will be 21 days for all treatments. Treatment will
continue, with tumor assessment every 6 ± 1 weeks, irrespective of regimen,
until disease progression or until other withdrawal criteria are met (including
completion of a single-agent chemotherapy regimen). If clinical progression is
diagnosed then confirmation of disease progression with a computed tomography
(CT) scan (per RECIST Version 1.1) will be required. Tumor scan at the
End-of-Treatment Visit is not required if patient had radiographic evidence of
disease progression on study, or it has been < 2 weeks since last on-study
scan. In addition, a magnetic resonance imaging (MRI) may be used in place of a
CT at end-of-treatment scan if required per local authorities.
Patients may opt to continue to receive treatment with rociletinib following
radiographic progression as outlined in the National Comprehensive Cancer
Network (NCCN) guidelines for treatment of NSCLC with EGFR TKIs if: a) the
patient provides additional consent, b) the investigator feels it is in the
patient*s best interest, and c) the sponsor provides approval. In general,
eligible patients may include those with asymptomatic systemic progression or
locally symptomatic progression, such as brain metastases amenable to local
treatment, with concomitant asymptomatic systemic progression or continued
systemic disease control.
Patients randomized to the comparator chemotherapy arm may choose to cross over
to receive rociletinib upon radiological progression. As with all patients, if
clinical progression is diagnosed then confirmation of disease progression with
a CT/MRI scan (per RECIST 1.1) will be required along with sponsor approval
before crossing over to treatment with rociletinib. For patients who cross
over, the starting dose of rociletinib (500 mg BID vs. 625 mg BID) will be the
choice of the investigator.
When protocol specified therapy is discontinued, and the patient has yet to
progress, patients will continue to undergo scheduled tumor assessments for
monitoring of PFS. All patients will also be followed for survival status, and
subsequent NSCLC cancer therapy.
Dosing may be delayed or reduced according to protocol-specified toxicity
criteria.
Patients will undergo serial assessments for anti-tumor efficacy, drug safety,
and PROs. Sparse blood sampling for POPPK analyses will be conducted in all
patients treated with rociletinib. A central laboratory will confirm presence
or absence of the T790M mutation in formalin-fixed paraffin embedded (FFPE)
tumor tissue. While results of the testing are not required prior to
randomization, the tissue sample must be submitted to the central laboratory
prior to randomization. Local laboratories will be used for hematology and
chemistry. ECGs will be performed and interpreted locally for patient care
decisions; however, tracings will be collected centrally for independent
evaluation. Tumor scans will be acquired by the investigative site and
evaluated locally for patient treatment decisions. Scans will also be collected
and stored with a central vendor and quality control performed; central reading
of scans will not be done unless requested by the sponsor. Following disease
progression, patients who provide additional consent will undergo tumor biopsy
before subsequent-line therapy is initiated.
AEs will be collected from the time the first dose of study drug is
administered through to 28 days after the last protocol-specified treatment
administration. Study procedure related AEs that occur after signing of the
Informed Consent Form (ICF) but before administration of study drug will also
be captured.
An Independent Data Monitoring Committee (IDMC) will review safety and efficacy
data on a periodic basis to ensure an acceptable overall risk and benefit for
patients participating in the study; however no formal analysis for futility or
efficacy is planned. The IDMC will also monitor on an ongoing basis the
proportion of T790M positive and T790M negative patients enrolled into the
study, in order to ensure adequate enrollment of T790M positive patients. If an
imbalance in enrollment by T790M status is observed, further enrollment may be
restricted to T790M positive patients only.
Intervention
Patients will be randomized 1:1:1 to receive either rociletinib 500 mg BID,
rociletinib 625 mg BID, or single-agent cytotoxic chemotherapy (investigator
choice of pemetrexed, gemcitabine, docetaxel, or paclitaxel; choice of
chemotherapy agent must be specified before randomization).
Rociletinib
Daily oral rociletinib at either 500 mg BID or 625 mg BID with 8 oz (240 mL) of
water and with a meal or within 30 minutes after a meal. Treatment with
rociletinib is continuous and each cycle will comprise of 21 days.
Pemetrexed
500 mg/m2 pemetrexed given intravenously on Day 1 of each 21-day cycle.
Gemcitabine
1250 mg/m2 gemcitabine given intravenously on Days 1 and 8 of each 21-day cycle.
Docetaxel
75 mg/m2 docetaxel (60 mg/m2 for patients residing in East-Asian territories)
given intravenously on Day 1 of each 21-day cycle, or 35 mg/m2 docetaxel given
intravenously on a weekly basis as part of a continuous 21 day cycle; ie,
dosing will be on Days 1, 8, and 15 of each 21 day cycle.
Paclitaxel
80 mg/m2 paclitaxel given intravenously as a 1 hour infusion, on a weekly basis
as part of a continuous 21 day cycle; ie, dosing will be on Days 1, 8, and 15
of each 21-day cycle.
Study burden and risks
To date, approximately 472 patients with NSCLC have received at least one dose
of rociletinib. Commonly reported side effects in these patients, which may
have been due to taking the study drug, are listed below. However, since
rociletinib is an experimental drug, not all side effects are known, and there
is a risk that rare or previously unknown side effects may occur. It is
important that you tell the study doctor or study staff about any side effects
you are experiencing, even if you do not think they are due to taking the study
drug
Common (>=20% of patients)
• Nausea
• Hyperglycemia (high blood glucose which is the same as high levels of sugar
in the blood): High blood glucose can cause symptoms such as nausea, vomiting
and feeling tired. You must tell your doctor if you notice any of these
symptoms as it could be a sign your blood glucose is increasing. You may be
asked to take another medicine to control high blood glucose levels.
• Feeling tired (fatigue)
• Loose stools (diarrhea)
• Changes in your ECG (electrocardiogram - tracing of your heart rhythm). Some
patients experienced a lengthening of the waves in their ECG tracings, called
increase in QT. In severe cases, this can cause changes to the rhythm of your
heart; in rare instances, could result in death. You will be carefully
monitored in the study for any changes to your ECG
Less common (5-19% of patients)
• Decrease in appetite
• Muscle spasms
• Vomiting
• Weight Loss
• Joint or muscle pain
• Dizziness
• Changes in blood tests that measure how well your kidney and liver are
functioning
• Low blood counts (red blood cells, white blood cells and platelets )
• A low red blood cell count may make you feel tired or dizzy
• A low white blood cell count puts you at higher risk for infection
• A low platelet count affects the ability of your blood to clot and could lead
to bleeding events
Rare (<5% of patients)
• Constipation
• Headache
• Rash
• Change in sense of taste
• Insomnia (difficulty sleeping)
• Lung inflammation (pneumonitis). Patients taking rociletinib who developed
pneumonitis have recovered, but this event could be very serious and could
result in death in rare cases
• Pancreatitis (inflammation of your pancreas, which in one patient resulted
in death)
• Cataract (Clouding of the lens of the eye)
5500 Flatiron Parkway Suite 100
Boulder 80301 CO
US
5500 Flatiron Parkway Suite 100
Boulder 80301 CO
US
Listed location countries
Age
Inclusion criteria
All patients must meet all of the following inclusion criteria:
1. Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with radiological progression on the most recent therapy received
2. Documented evidence of a tumor with 1 or more EGFR activating mutations excluding exon 20 insertion
3. Disease progression confirmed by radiological assessment while receiving treatment with single-agent EGFR-TKI (eg, erlotinib, gefitinib, afatinib, or dacomitinib) or EGFR TKI in combination with other targeted therapy (eg, bevacizumab, immunotherpay). The washout period for the single agent EGFR-TKI and combination targeted therapy is a minimum of 3 days or 5 half lives, whichever is more applicable, prior to start of treatment.
4. Multiple lines of prior treatment are permitted and there is no specified order of treatment, but in the course of their treatment history, patients must have received and have radiologically documented disease progression following:
- At least 1 line of prior treatment with a single-agent EGFR TKI (eg, erlotinib, gefitinib, afatinib, or dacomitinib) or EGFR TKI in combination with other targeted therapy (eg, bevacizumab, immunotherapy)
o If EGFR-TKI is a component of the most recent treatment line, the washout period for the EGFR-TKI is a minimum of 3 days before the start of study drug treatment
AND
- A platinum-containing doublet chemotherapy (either progressed during therapy or completed at least 4 cycles without progression with subsequent progression after a treatment-free interval or after a maintenance treatment).
o If cytotoxic chemotherapy is a component of the most recent treatment line, treatment with chemotherapy should have been completed at least 14 days prior to start of study treatment. When an EGFR TKI is given in combination with platinum-containing doublet chemotherapy, treatment with the EGFR TKI may continue until at least 3 days before start of treatment.
5. Have undergone a biopsy of either primary or metastatic tumor tissue within 60 days prior to start of treatment and have tissue sent to the central laboratory prior to randomization
6. Measureable disease according to RECIST Version 1.1
7. Life expectancy of at least 3 months
8. ECOG performance status of 0 to 1
9. Age >= 18 years (in certain territories, the minimum age requirement may be higher eg, age >= 20 years in Japan and Taiwan, age >= 21 years in Singapore)
10. Patients should have recovered to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade <= 1 from any significant chemotherapy-related toxicities
11. Adequate hematological and biological function, confirmed by the following local laboratory values:
Bone marrow function
a. Absolute neutrophil count (ANC) >= 1.5 × 109/L
b. Platelets > 100.0 × 109/L
c. Hemoglobin >= 9 g/dL (or 5.6 mmol/L)
Hepatic function
d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 3 × upper limit of normal (ULN); if liver metastases, <= 5 × ULN
e. Bilirubin <= 2 × ULN
* Patients with documented Gilbert*s syndrome and conjugated bilirubin within the normal range may be allowed into the study. In this event, it will be documented that the patient was eligible based on conjugated bilirubin levels
Renal function
f. Creatinine clearance >= 45 mL/min
Electrolytes
g. Potassium and magnesium within normal range. Patients may receive supplements to meet this requirement.
Glucose
h. Fasting serum glucose <= 160 mg/dL (8.9 mmol/L)
i. Glycosylated hemoglobin (HgbA1C) < 8%
12. Written consent on an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved ICF before any study specific evaluation
Exclusion criteria
Any of the following criteria will exclude patients from study participation:
1. Any other malignancy associated with a high mortality risk within the next 5 years and for which the patients may be (but not necessarily) currently receiving treatment
* Patients with a history of malignancy that has been completely treated, with no evidence of that cancer currently, are permitted to enroll in the trial provided all chemotherapy was completed > 6 months prior and/or bone marrow transplant > 2 years prior
2. Known pre-existing interstitial lung disease
3. Tumor small cell transformation by local assessment, irrespective of presence of T790M-positive component
4. Patients with leptomeningeal carcinomatosis are excluded. Other central nervous system (CNS) metastases are only permitted if treated, asymptomatic, and stable (not requiring steroids for at least 2 weeks prior to randomization and the patient is neurologically stable; ie, free from new symptoms of brain metastases). If a patient has had brain metastasis treated within the previous 8 weeks, a follow-up scan must have been performed to confirm that treated metastasis remain controlled without evidence of new lesions.
5. Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and that treatment cannot be either discontinued or switched to a different medication (known to have no effect on QT) before starting protocol specified treatment (see http://crediblemeds.org/ for a list of QT-prolonging medications)
6. Prior treatment with rociletinib, or other drugs that target T790M-positive mutant EGFR with sparing of WT EGFR including but not limited to osimertinib, HM61713, and TAS-121
7. Any contraindications for therapy with pemetrexed, paclitaxel, gemcitabine or docetaxel unless a contraindication with respect to one of these drugs will not affect the use of any of the others as a comparator to rociletinib
8. Any of the following cardiac abnormalities or history:
a. Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia*s method (QTCF) > 450 msec
b. Inability to measure QT interval on ECG
c. Personal or family history of long QT syndrome
d. Implantable pacemaker or implantable cardioverter defibrillator
e. Resting bradycardia < 55 beats/min
9. Non-study related surgical procedures <= 7 days prior to randomization. In all cases, the patient must be sufficiently recovered and stable before treatment administration.
10. Females who are pregnant or breastfeeding
11. Refusal to use adequate contraception for fertile patients (females and males) while on treatment and for 6 months after the last dose of study treatment (rociletinib and chemotherapy irrespective of single cytotoxic agent used)
12. Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study, e.g., substance abuse, uncontrolled intercurrent illness including:
• uncontrolled diabetes
• active infection
• arterial thrombosis, and
• symptomatic pulmonary embolism
13. Any other reason the investigator considers the patient should not participate in the study
14. Treatment with live vaccines initiated less than 4 weeks prior to randomization
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 | EUCTR2014-003437-26-NL |
| ClinicalTrials.gov | NCT02322281 |
| CCMO | NL52061.042.15 |