| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Previously treated locally advanced and unresectable or metastatic nonsmall
cell lung cancer (NSCLC) with KRAS p.G12C mutation |
|
| E.1.1.1 | Medical condition in easily understood language |
Previously treated locally advanced and unresectable or metastatic nonsmall
cell lung cancer (NSCLC) with KRAS p.G12C mutation |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| •To compare the efficacy of AMG 510 versus docetaxel as assessed by progression-free survival (PFS) in previously treated subjects with KRAS p.G12C mutated nonsmall cell lung cancer (NSCLC) |
|
| E.2.2 | Secondary objectives of the trial |
•To compare the efficacy of AMG 510 Versus docetaxel as assessed by:
- Overall Survival (OS)
- Objective response rate (ORR)
•To compare patient-reported outcomes (PRO) as assessed by:
- European Organization for Research and Treatment of Cancer Quality of life Questionnaire Core 13 (EORTC QLQ-LC13) and European
Organization for Research and Treatment of Cancer Quality-of-life
Questionnaire Core 30 (EORTC QLQ-C30)
•To compare efficacy of AMG 510 versus docetaxel as assessed by:
- duration of response (DOR), time to response (TTR), and disease control rate (DCR)
•To compare the safety and tolerability of AMG 510 versus docetaxel
•To compare the effect of treatment with AMG 510 on other treatment
and disease related symptoms, and health related quality of life relative to docetaxel
•To characterize the pharmacokinetics (PK) of AMG 510 and its major metabolites |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Optional sub-study within current protocol. Sub-study Assessing
Exploratory Biomarkers in Tumor Biopsies at Progression. In order to
better understand mechanisms of resistance, any patients with lesions
amenable to biopsy will be invited to participate in this sub-study at the
discretion of the investigators. |
|
| E.3 | Principal inclusion criteria |
• Subject or subject's legally acceptable representative has provided
informed consent prior to initiation of any study specific
activities/procedures.
• Age ≥ 18 years of age
• Have documentation of KRAS p.G12C mutation confirmed by central
testing through the current protocol or have documentation of KRAS
p.G12C mutation through Amgen Study 20190294 prior to enrollment.
• Subjects will have received and progressed or experienced disease
recurrence on or after receiving at least 1 prior systemic therapy for
locally advanced and unresectable or metastatic disease. Prior treatment
must include a platinum-based doublet chemotherapy and checkpoint
inhibitor for advanced or metastatic disease, either given as one line of
therapy or as individual lines of therapy unless the subject has a medical
contraindication to one of the required therapies. If the subject has a
medical contraindication to a required therapy, the subject may be
enrolled only after the investigator discusses and obtains approval from
the Amgen medical monitor.
a) Adjuvant therapy will count as a line of therapy if the subject
progressed on or within 6 months of adjuvant therapy administration.
b) In locally advanced and unresectable NSCLC, disease progression on
or within 6 months of end of prior curatively intended multimodal
therapy will count as a line of therapy. If chemoradiation is followed by
planned systemic therapy without documented progression between
chemoradiation and systemic therapy, the entire treatment course
counts as one line of therapy.
• Subjects must have archived tumor tissue samples (formalin fixed,
paraffin embedded [FFPE] sample [FFPE of excisional, core needle, or
fine needle aspirates] collected within 5 years) or be willing to undergo
pre-treatment tumor biopsy (excisional, core needle, or fine needle
aspirates) prior to enrollment.
• Measurable disease per RECIST v1.1 criteria. Lesions previously
radiated are not considered measurable unless they have progressed
after radiation.
• ECOG Performance Status of ≤ 1
• Adequate hematologic laboratory assessments
• Life expectancy of > 3 months, in the opinion of the investigator
• Adequate liver function
• International normalized ratio (INR) and activated partial
thromboplastin time ≤ 1.5 x ULN
• Serum creatinine ≤ 1.5 x ULN OR creatinine clearance ≥ 60 mL/min.
Cockcroft-Gault formula will be used for creatinine clearance calculation.
Twenty-four hour urine collection is not required but is allowed.
• QTc ≤ 470 msec in females and ≤ 450 msec in males
• Ability to take oral medications and willing to record daily adherence
to investigational product |
|
| E.4 | Principal exclusion criteria |
• Subjects have received prior docetaxel in unresectable or metastatic
setting.
• Mixed small-cell lung cancer or mixed NSCLC histology
• Previously identified driver mutation (according to local standard of
care or guidelines) other than KRAS p.G12C for which an approved
therapy is available (including EGFR, ALK, etc).
• Active brain metastases. Subjects who have had brain metastases
resected or have received whole brain radiation therapy ending at least
4 weeks (or stereotactic radiosurgery ending at least 2 weeks) prior to
study day 1 are eligible if they meet all of the following criteria: a)
residual neurological symptoms grade ≤ 2; b) on stable doses of dexamethasone or equivalent for at least 2 weeks, if applicable; and c)
follow-up MRI performed within 30 days prior to enrollment shows no
progression or new lesions appearing.
• Leptomeningeal disease.
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring
recurrent drainage procedures at a frequency greater than monthly.
Subjects with PleurX catheters in place may be considered for the study
with Medical Monitor approval.
Other Medical Conditions
• Known history of Human Immunodeficiency Virus (HIV) infection
• Exclusion of hepatitis infection based on the following results and/or
criteria:
a) Positive hepatitis B surface antigen (HepBsAg)
b) Negative HepBsAg with a positive for hepatitis B core antibody
(Hepatitis B core antibody testing is not required for screening, however
if this is done and is positive, then hepatitis B surface antibody [Anti-
HBs] testing is necessary. Undetectable anti HBs in this setting would
suggest unclear and possible infection, and needs exclusion).
c) Positive Hepatitis C virus antibody: Hepatitis C virus RNA by
polymerase chain reaction is necessary. Detectable Hepatitis C virus RNA
renders the subject ineligible.
If above antibody/antigen testing is not able to be obtained, positive
hepatitis B or C viral load
• Malignancy other than NSCLC within 3 years prior to randomization,
with the exception of those with a negligible risk of metastases or death
and treated with expected curative outcome.
• Major surgery within 28 days of study day 1
• Significant gastrointestinal disorder that results in significant
malabsorption, requirement for intravenous alimentation, or inability to
take oral medication.
• Significant cardiovascular disease, such as New York Heart Association
cardiac disease (Class II or greater), myocardial infarction within 6
months prior to study day 1, unstable arrhythmias or unstable angina.
• Severe infections within 4 weeks prior to randomization including, but
not limited to hospitalization for complications of infection, bacteremia
or severe pneumonia.
• Therapeutic oral or intravenous antibiotics within 2 weeks prior to
randomization. Prophylactic antibiotics are allowed with Amgen medical
monitor approval.
• Current CTCAE version 5.0 grade ≥ 2 peripheral neuropathy
Prior/Concomitant Therapy
• Unresolved toxicities from prior anti-tumor therapy, defined as not
having resolved to CTCAE version 5.0 grade 0 or 1, or to levels dictated
in the eligibility criteria with the exception of alopecia (any grade
allowed) or toxicities from prior anti-tumor therapy that are considered
irreversible (defined as having been present and stable for > 6 months),
endocrine adverse events that are stably maintained on appropriate
replacement therapy.
• Anti-tumor therapy within 4 weeks of study day 1; Please note that
bisphosphonates or anti-Receptor Activator of Nuclear Factor Kappa Beta
Ligand (anti RANKL) antibody therapy is allowed if needed for
management of hypercalcemia or for prevention of skeletal events.
• Therapeutic or palliative radiation therapy within 2 weeks of study day
1. Subjects must have recovered from all radiotherapy related toxicity to
CTCAE version 5.0 grade 1 or less with the exception of alopecia (any
grade of alopecia allowed).
• Other investigational procedures are excluded
• Previous treatment with AMG 510 or other KRAS G12C inhibitor
• History of severe hypersensitivity to docetaxel or to other drugs
formulated with polysorbate 80, or known sensitivity to any of the products or components to be administered during dosing.
• Use of known cytochrome P450 (CYP) 3A4 or P-gp sensitive substrates
(with a narrow therapeutic window), within 14 days or 5 half-lives of the
drug or its major active metabolite, whichever is longer, prior to study
day 1 that was not reviewed and approved by the principal investigator
and the Amgen medical monitor.
• Use of strong inducers of CYP3A4 (including herbal supplements such
as St. John's wort) within 14 days or 5 half-lives (whichever is longer)
prior to study day 1 that was not reviewed and approved by the principal
investigator and the Amgen medical monitor.
• Use of warfarin. Other anticoagulation may be allowed withAmgen
medical monitor approval |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • PFS - defined as time from randomization until disease progression or death from any cause, whichever occurs first for all subjects. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The timing for the PA of PFS will be event driven. If PFS early success is
achieved in the IA, the IA will serve the purpose of PA of PFS.
The final analysis of the study will be done when the last subject
completes LTFU. |
|
| E.5.2 | Secondary end point(s) |
• Overall survival - defined as time from randomization until death from any cause.
• Objective response (complete response [CR] + partial response [PR]), assessed per RECIST v1.1. Response will be assessed by BICR.
• Change from baseline over time to week 12 in disease related symptoms of:
o Dyspnea as measured by a 4 item dyspnea domain from QLQ-C30 and QLQ-LC13
o Cough as measured by QLQ-LC13
o Chest Pain as measured by QLQ-LC13
• Change from baseline over time to week 12 in
o Physical functioning as measured by QLQ-C30
o Global health status as measured by QLQ-C30
• Duration of response - defined as time from first evidence of PR or CR to disease progression or death due to any cause, whichever occurs first. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The timing for the PA of PFS will be event driven. If PFS early success is achieved in the IA, the IA will serve the purpose of PA of PFS.
The final analysis of the study will be done when the last subject completes LTFU. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 160 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Switzerland |
| Taiwan |
| Australia |
| Belgium |
| Brazil |
| Canada |
| China |
| Denmark |
| Finland |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Portugal |
| Russian Federation |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of study date is defined as the date when the last subject
across all sites is assessed or receives an intervention for evaluation in
the study (ie, last subject last visit), following any additional parts in
the study (eg, LTFU, additional antibody testing), as applicable. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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