To evaluate the efficacy and safety of tucatinib in combination with trastuzumab and mFOLFOX6 in comparison to mFOLFOX6 given with or without either bevacizumab or cetuximab as first-line (1L) treatment in adults with HER2 positive (HER2+)…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Gastrointestinal disorders, Colorectal Cancer
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Objective:
To compare progression-free survival (PFS) per Response Evaluation Criteria in
Solid Tumors 1.1 (RECIST v1.1) according to blinded independent central review
(BICR) assessment between treatment arms.
Secondary outcome
Secondary Objectives:
• To compare overall survival (OS) between treatment arms
• To compare confirmed objective response rate (cORR) per RECIST v1.1 according
to BICR assessment between treatment arms
• To assess PFS per RECIST v1.1 according to investigator (INV) assessment
• To evaluate cORR per RECIST v1.1 according to INV assessment
• To evaluate duration of response (DOR) per RECIST v1.1 according to BICR
assessment
• To evaluate DOR according to INV assessment
• To evaluate time from randomization to disease progression on next-line
treatment or death from any cause (PFS2)
• To assess the overall safety profiles by the treatment arms
• To evaluate the pharmacokinetics (PK) of tucatinib
• To assess the change from baseline in selected items of the global health
status/quality of life (QoL), physical functioning, and appetite loss by
treatment arms using the European Organization for Research and Treatment of
Cancer Quality of Life 30-item core questionnaire (EORTC QLQ-C30)
• To assess the time to meaningful change in global health status/QoL, physical
functioning and appetite loss by treatment arms using the EORTC QLQ-C30
Background summary
Please refer to Protocol Section 5. INTRODUCTION
Study objective
To evaluate the efficacy and safety of tucatinib in combination with
trastuzumab and mFOLFOX6 in comparison to mFOLFOX6 given with or without either
bevacizumab or cetuximab as first-line (1L) treatment in adults with HER2
positive (HER2+) metastatic colorectal cancer (mCRC).
Study design
Study Design:
This is a global, open label, randomized, phase 3, multicenter study to
evaluate the efficacy and safety of tucatinib in combination with trastuzumab
and mFOLFOX6 in comparison to mFOLFOX6 given with or without either bevacizumab
or cetuximab as 1L treatment in adults with HER2+ mCRC. Eligible participants
must have locally advanced unresectable or metastatic colorectal cancer (mCRC)
that is HER2+, RAS WT, and must not have received systemic treatment for CRC in
the metastatic setting except for a maximum of 2 doses of mFOLFOX6 in the
locally advanced unresectable or metastatic setting prior to randomization.
HER2 status will be determined via central lab testing during the screening
period using investigational HER2 immunohistochemistry (IHC) and in situ
hybridization (ISH) assays to support companion diagnostic development. The
American Society of Clinical Oncology/College of American Pathologists
(ASCO/CAP) gastric and gastroesophageal cancer guidelines will be used to
identify participants who are HER2+ with an immunohistochemistry (IHC) 3+ or
IHC 2+/in situ hybridization positive (ISH+) result. Participants are required
to have RAS WT status as determined by local or central testing; central
testing may only be used with Medical Monitor approval if local testing is not
available or when otherwise deemed necessary (for central RAS testing, tissue
must be submitted prior to study enrollment and must be analyzed within 1 year
of biopsy date).
The study consists of 2 arms. Approximately 400 participants will be randomized
in a 1:1 fashion to either the tucatinib experimental arm or the standard of
care (SOC) control arm. Randomization will be stratified by the following
factors: primary tumor location (left sided versus all other [right,
transverse, overlapping]), presence or absence of liver metastases, and number
of doses of mFOLFOX6 chemotherapy prior to randomization (0, 1, or 2).
Participants in the tucatinib experimental arm will receive tucatinib in
combination with trastuzumab and mFOLFOX6. Participants in the SOC control arm
will receive mFOLFOX6 given with or without either bevacizumab or cetuximab per
investigator*s decision. The regimen to be used in the SOC control arm should
be chosen before randomization, and all SOC regimens must start at doses
stipulated in the protocol. Participants must remain on their originally
assigned treatment regimen; however, individual components within a regimen may
be discontinued at the discretion of the investigator if it is in the
participant*s best interest. Crossover from the SOC control arm to the
tucatinib experimental arm is not permitted. Participants may be rescreened
once after initially failing to meet the inclusion/exclusion criteria.
Higher than expected incidence rate of adverse events of diarrhea have been
observed in participants with advanced gastrointestinal (GI) cancers who
received the combination of tucatinib, trastuzumab, and FOLFOX in an ongoing
phase 1b/2 study. In the current phase 3 study, antidiarrheal prophylaxis with
loperamide will be required for all participants on the tucatinib experimental
arm for Cycle 1 of study treatment only. The dosing of loperamide will be
adjusted by the investigator for all subsequent cycles, as appropriate.
Intervention
The study consists of 2 arms. Approximately 400 subjects will be randomized in
a 1:1 fashion to either the tucatinib experimental arm or the standard of care
(SOC) control arm.
Tucatinib experimental arm:
Tucatinib will be administered at a dose of 300 mg orally (PO) twice daily
(BID). Trastuzumab will be administered every 3 weeks (Q3W), with a loading
dose of 8 mg/kg intravenously (IV) on Cycle 1 Day 1 only, followed by 6 mg/kg
IV on Cycle 1 Day 22 then Day 1 and Day 22 of each
subsequent 6-week (42-day) cycle thereafter, except in specific circumstances
where trastuzumab may be give weekly to compensate for modifications in
treatment schedule. mFOLFOX6 will be administered every 2 weeks on Days 1, 15,
and 29 of each 6-week (42-day) cycle and
consists of oxaliplatin 85 mg/m2 IV, leucovorin 400 mg/m2 IV (or
levoleucovorin 200 mg/m2 IV; leucovorin or levoleucovorin is administered
concurrently with oxaliplatin via separate IV lines), 5-fluorouracil 400 mg/m2
(IV bolus), then 5-fluorouracil 2400 mg/m2 (IV administration over 46-48
hours).
Beginning on Cycle 1 Day 1, for all participants in the tucatinib experimental
arm, loperamide will be administered at a dose of 4 mg three times daily for
the first 14 days (Days 1-14), followed by 4 mg twice daily on Days 15-42.
Standard of care (SOC) control arm:
Participants randomized to the SOC control arm will receive mFOLFOX6 given with
or without either bevacizumab or cetuximab at the investigator*s discretion.
The investigator*s choice of control arm regimen must be made prior to
randomization. Participants must remain on their originally assigned treatment
regimen; however, individual components within a regimen may be discontinued at
the discretion of the investigator if it is in the participant*s best interest.
mFOLFOX6 will be administered every 2 weeks on Days 1, 15, and 29 of each 6
week (42 day) cycle and consists of oxaliplatin 85 mg/m2 IV, leucovorin 400
mg/m2 IV (or levoleucovorin 200 mg/m2 IV; leucovorin or levoleucovorin is
administered concurrently with oxaliplatin via separate IV lines), 5
fluorouracil 400 mg/m2 (IV bolus), then 5 fluorouracil 2400 mg/m2 (IV
administration over 46-48 hours).
Bevacizumab 5 mg/kg will be administered IV every 2 weeks (Days 1, 15, and 29
of each 6 week [42 day] cycle) during each 6 week (42 day) cycle.
Cetuximab will be administered 400 mg/m2 IV over 2 hours on Cycle 1 Day 1,
followed by 250 mg/m2 IV over 1 hour for each subsequent weekly dose during
each 6 week (42 day) cycle.
All subjects will be receive a radiographic assessment for progressive disease
per blinded independent central review (BICR). They will be subjected to a
safety and survival follow-up (follow-up will include assessment of PFS2).
Subjects may continue on treatment until disease progression per RECIST v1.1 by
BICR, unacceptable toxicity, withdrawal of consent, or study termination,
whichever occurs first
Study burden and risks
TUCATINIB COMMONLY REPORTED RISKS AND SIDE EFFECTS:
Most of the people who took tucatinib were cancer patients. Some people who
took tucatinib were healthy volunteers who did not have cancer.
Patients with cancer who were treated with only tucatinib included 50 patients
in total. These patients had the side effects listed below.
These side effects may or may not be directly related to tucatinib. They could
be related to cancer or other medical problems.
- Feeling sick to stomach (nausea)
- Watery poop (diarrhea)
- Feeling tired (fatigue)
- Throwing up (vomiting)
- Rash
- Difficulty pooping (constipation)
- Cough
- Pain in arms or legs (pain in extremity)
- Back pain
- Headache
- Infection that could cause frequent and painful urination (urinary tract
infection)
- Muscle pain (myalgia)
- Muscle and bone pain in chest (musculoskeletal chest pain)
- Belly pain (abdominal pain)
- High levels of liver enzymes (increased liver function tests). This may mean
the patient has a problem with his/her liver.
- Not wanting to eat (anorexia)
- Feeling dizzy (dizziness)
- Feeling out of breath (dyspnea)
- Patchy redness on skin (erythema)
- Low levels of magnesium in your blood (hypomagnesemia). Participants may feel
weak, have an abnormal heartbeat, muscle cramps, or seizures.
- Heavy sweating while sleeping (night sweats)
- Infection in the nose, sinuses or throat (upper respiratory tract infection).
Participants may have fever, pain, or a hard time breathing.
Also liver function problems, severe diarrhea and increased creatinine levels
have been reported.
The other drugs used in this study (trastuzumab, mFOLFOX6 (which consists of
oxaliplatin, leucovorin or levoleucovorin, and fluorouracil), cetuximab and
bevacizumab) can also have side effects. As these are marketed drugs, please
refer to the Patient Information Leaflet.
RISKS AND SIDE EFFECTS OF TUCATINIB, TRASTUZUMAB AND MFOLFOX6 TOGETHER:
There may also be side effects that come from getting tucatinib with
trastuzumab, and mFOLFOX6 that are not found (or are not as serious) in people
who only take one of these drugs.
RISKS OF THE EXPERIMENTAL HER2 ASSAYS:
These experimental tests will check to see if participants' cancer cells make
HER2. These tests are still being developed for your disease. There is a chance
that the test might not work to find participants who are most likely to
respond to the study drugs.
RISKS OF THE TUMOR BIOPSY:
The risks of tumor biopsy include possible pain, discomfort, bleeding,
swelling, scarring, bruising and infection. To reduce these risks, the site of
the biopsy will be numbed, and sterile techniques will be used.
Furthermore participants may have discomforts from the intravenous infusion or
blood draws (irritation or bruises); from the CT scans or MRIs (claustrophobic
sensation, reactions to the contrast agent, minimal radiation risk), from the
MUGA scan (reaction to tracer, minimal radiation risk) or from the ECG (skin
irritation, slight redness or burning of the skin at the site where the leads
were attached).
30th Drive SE 21823
Bothell 98021
US
30th Drive SE 21823
Bothell 98021
US
Listed location countries
Age
Inclusion criteria
Inclusion Criteria
Participants must meet the following key inclusion criteria to be eligible for
the study:
• Have histologically and/or cytologically documented adenocarcinoma of the
colon or rectum, which is locally advanced unresectable or metastatic
• Participants must be willing and able to provide the most recently available
formalin fixed paraffin embedded tumor tissue blocks (or freshly sectioned
slides, see laboratory manual for details), obtained prior to treatment
initiation, to a sponsor designated central laboratory for biomarker analysis.
If archival tissue is not available, then a newly obtained baseline biopsy of
an accessible tumor lesion is required within 35 days prior to the Cycle 1 Day
1 timeframe. Biopsy must provide adequate tissue for analysis; the following
biopsy types are acceptable: resection, excision, punch (skin lesions only) and
core needle biopsies.
• Have HER2+ disease as determined by tissue based investigational HER2 IHC and
ISH assays performed at a sponsor defined central laboratory. HER2
amplification will be determined using ASCO/CAP guidelines for gastric and
gastroesophageal cancer with IHC 3+ or IHC 2+/ISH+ result.
• Have RAS WT disease as determined by local or central testing. Central
testing may only be used with Medical Monitor approval if local testing is not
available or when otherwise deemed necessary. For central RAS testing, tissue
must be submitted prior to study enrollment and analyzed within 1 year of
biopsy date.
• Have radiographically measurable disease per RECIST v1.1 according to INV
assessment, with at least one site of disease that is measurable and that has
not been previously irradiated; or, if the participant has had previous
radiation to the target lesion(s), there must be evidence of progression since
the radiation
• Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• CNS Inclusion*Based on screening contrast brain magnetic resonance imaging
(or CT with contrast if MRI is contraindicated), participants may have any of
the following:
a. No evidence of brain metastases
b. Previously treated brain metastases which are asymptomatic
* Brain metastases previously treated with local therapy must not have
progressed since treatment
* Time since whole brain radiation therapy (WBRT) is >= 14 days prior to
enrollment, time since stereotactic radiosurgery (SRS) is >= 7 days prior to
enrollment, or time since surgical resection is >= 28 days prior to enrollment
* Relevant records of any CNS treatment must be available to allow for
classification of target and non target lesions
Exclusion criteria
Exclusion Criteria
Participants will be excluded from the study for any of the following key
exclusion criteria reasons:
• Have previously received any systemic anticancer therapy for CRC in the
locally advanced unresectable or metastatic setting or have participated in any
interventional clinical trial for CRC in the locally advanced unresectable or
metastatic setting; note that participants may have received a maximum of 2
doses of mFOLFOX6 in the locally advanced unresectable or metastatic setting
prior to randomization.
Note: participants may have received prior chemotherapy for CRC in the adjuvant
setting provided that it was completed >6 months prior to enrollment.
• Have previously received radiation therapy within 14 days prior to enrollment
(or within 7 days in the setting of SRS). Participants who have received prior
radiation therapy must have recovered to baseline from any treatment related
adverse events (AEs). Participants who have received palliative radiotherapy
for symptomatic metastases may enter the study without a washout period
provided that the participant has recovered from any treatment related AEs.
• Have previously been treated with anti HER2 therapy
• Have ongoing >= Grade 2 diarrhea of any etiology
• Inability to swallow pills or any significant GI disease which would preclude
the adequate oral absorption of medications
• Participants with active CNS metastases (irradiated or resected lesions are
permitted, See Inclusion Criteria for details). Participants with carcinomatous
meningitis are excluded without exception.
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 | EUCTR2021-002672-40-NL |
| ClinicalTrials.gov | NCT05253651 |
| CCMO | NL81869.000.23 |