| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| KRAS p.G12C mutant advanced NSCLC, CRC, and other solid tumors |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-small cell lung cancer, colorectal cancer and other solid tumors |
|
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061451 |
| E.1.2 | Term | Colorectal 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 |
Phase1
Part 1 (a,b,d) / 2 (a,b,d)
To evaluate the safety & tolerability of AMG 510 in adult subjects with KRAS p.G12C mutant advanced solid Tumors
To estimate the MTD and/or a RP2D in adult subjects with KRAS p.G12C mutant advanced solid Tumors
1c/2c
To evaluate the safety & tolerability of AMG 510 in combination with pembrolizumab in adult subjects with KRAS p.G12C mutant advanced NSCLC
2e
To evaluate the safety & tolerability of AMG 510 in adult subjects with previously untreated, KRAS p.G12C mutant metastatic NSCLC
To evaluate tumor response assessed by RECIST1.1 of AMG 510 as monotherapy in adult subjects with previously untreated KRAS p.G12C mutant metastatic NSCLC
Phase 2 Part A
To evaluate tumor ORR assessed by RECIST1.1 criteria of AMG 510 as monotherapy in subjects with KRAS p.G12C mutated advanced tumors
Phase 2 Part B
To evaluate tumor ORR assessed by RECIST1.1 criteria of AMG 510 960 mg QD and 240 mg QD as monotherapy in previously treated subjects |
|
| E.2.2 | Secondary objectives of the trial |
Phase1
Part 1a/2a, 1b/2b & 1d/2d
To characterize the PK of AMG 510 as an oral tablet formulation
To evaluate tumor response assessed by RECIST 1.1 of AMG 510 as monotherapy in advanced solid tumors with KRAS p.G12C mutation
To evaluate the effect of food on the oral PK of AMG 510 and the relationship between changes in corrected QT interval & AMG 510 exposure
1c/2c
To characterize the PK of AMG 510 as an oral tablet formulation in combination with pembrolizumab
To evaluate tumor response assessed by RECIST 1.1 & other measures of efficacy of AMG 510 in combination with pembrolizumab in adult subjects with KRAS p.G12C mutant advanced NSCLC
2e
To characterize the PK of AMG 510 as an oral tablet formulation & the PK of midazolam when administered with & without AMG 510
Phase2
Part A
To evaluate other measures of AMG 510 efficacy as monotherapy in subject with KRAS p.G12C mutant advanced tumors by RECIST1.1
Part B
See protocol |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject has provided informed consent prior to initiation of any study specific activities/procedures
2. Men or women ≥ 18 years old
3. For all parts except 2e: Pathologically documented, locally-advanced or metastatic malignancy with, KRAS p.G12C mutation identified through molecular testing. For phase 2 Part A only, the mutation will be confirmed by central testing prior to enrollment for NSCLC and CRC tumor types only..
a. For NSCLC:
Phase 1 subjects must have received platinum-based combination therapy and/or targeted therapies (ie, if molecular testing has identified mutations in EGFR, ALK, or proto-oncogene tyrosine-protein kinase ROS [ROS1] or expression of programmed death-ligand [PD-L1]), prior to receiving AMG 510.
Phase 2 Part A subjects must have progressed after receiving anti-PD1 or anti-PD-L1 immunotherapy (unless contraindicated) AND/OR platinum-based combination chemotherapy AND targeted therapy if actionable oncogenic driver mutations were identified [ie, EGFR,
ALK, and ROS1]). Subjects in phase 2 Part A must have received no more than 3 prior lines of therapy. For all NSCLC subjects, the following guidance should be used:
• Adjuvant therapy will count as a line of therapy if the subject progressed on or within 6 months of adjuvant therapy administration.
• In locally advanced and unresectable NSCLC, disease progression on or within six 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 & systemic therapy, the entire treatment course counts as 1 line of therapy.
• Maintenance therapy following platinum doublet-based chemotherapy is not considered as a separate line of therapy.
b. For CRC:
Phase 1 subjects must have received at least 2 prior systemic regimens in the metastatic setting . For those CRC subjects with tumors that are MSI-H, at least 1 of the prior systemic regimens must be treatment with either nivolumab or pembrolizumab if they were clinically able to receive inhibitors and 1 of these agents is approved for that indication in the region or country.
Phase 2 subjects must have progressed after receiving fluoropyrimidine AND oxaliplatin AND irinotecan. For those CRC
subjects with tumors that are MSI-H, at least 1 of the prior systemic regimens must have included an anti-PD1 therapy if they were clinically able to receive inhibitors and 1 of these agents is approved for that indication in the region or country.
c. For advanced solid tumor types other than NSCLC or CRC, subjects must have received at least one prior systemic therapy or be intolerant or ineligible for available therapies known to provide clinical benefit.
Subjects with advanced solid tumor types other than NSCLC or CRC may be enrolled and treated in phase 1 or phase 2 without central confirmation of the KRAS p.G12C mutation.
4. Subjects willing to provide archived tumor tissue samples (formalin fixed, paraffin embedded [FFPE] sample collected within 5 years) or willing to undergo pre- treatment tumor biopsy. Phase 1 subjects with all tumor types and phase 2 subjects with tumor types other than NSCLC or CRC with prior molecularly confirmed KRAS p.G12C mutation who do not have archived tissue available can be allowed to enroll without undergoing tumor biopsy upon agreement with investigator and the Medical Monitor if a tumor biopsy is not feasible.
5. Subjects who have lesions that can be feasibly biopsied will be asked to undergo an optional biopsy at the time of tumor progression.
6. Measurable disease per RECIST 1.1 criteria (Appendix D).
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 (phase 1) or ≤ 1 (phase 2 Part A)
8. Life expectancy of > 3 months, in the opinion of the investigator
9. Ability to take oral medications and willing to record daily adherence to investigational product utilizing a sponsor-provided dosing diary
10. QTc ≤ 470 msec (based on average of screening triplicates)
11. Adequate hematological laboratory assessments, as follows:
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Platelet count ≥ 75 x 109/L
• Hemoglobin ≥ 9 g/dL (90 g/L)
12. Adequate renal laboratory assessments, as follows:
• Estimated glomerular filtration rate based on MDRD (Modification of Diet in Renal Disease) calculation ≥ 60 ml/min/1.73 m2 (phase 1 and phase 2 Part A)
13. Adequate hepatic laboratory assessments, as follows:
• Aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN) (if liver metastases are present, ≤ 5 x ULN)
• Alanine aminotransferase (ALT) < 2.5 x ULN (if liver metastases are present, ≤ 5 x ULN)
• Total bilirubin < 1.5 x ULN (< 2.0 x ULN for subjects with documented Gilbert’s syndrome or < 3.0 x ULN for subjects for whom the indirect bilirubin level suggests an extrahepatic source of elevation)
See protocol for additional inclusion criteria. |
|
| E.4 | Principal exclusion criteria |
1. Active brain metastases from non-brain tumors.
2. History or presence of hematological malignancies unless curatively treated with no evidence of disease ≥ 2 years
3. Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure, unstable angina, or cardiac arrhythmia requiring medication
4. Gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for intravenous alimentation, uncontrolled inflammatory GI disease (eg, Crohn’s disease, ulcerative colitis)
5. Active infection requiring IV antibiotics within 1 weeks of study enrolment (day 1)
6. Exclusion of hepatitis infection,
7. Known positive test for HIV
8. 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.
9. Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy [except for subjects with breast cancer], or investigational agent) within 28 days of study day 1
10. Therapeutic or palliative radiation therapy within 2 weeks of study day 1. Subjects must have recovered from all radiotherapy related toxicity.
11. Currently enrolled in another investigational device or drug study, or less than 28 days since ending another investigational device or drug study(s), or receiving other investigational agent(s)
12. Other investigational procedures are excluded
13. Previous treatment with a KRASG12C inhibitor
14. Major surgery within 28 days of study day 1
15. Monotherapy with AMG 510: Men and women of childbearing potential (WOCBP) who are unwilling to practice acceptable methods of birth control during treatment and for at least 7 days (women) or 7 days (men) after receiving the last dose of AMG 510. Acceptable methods of highly effective birth control for women include sexual abstinence (refraining from heterosexual intercourse); vasectomy (women with a single male sexual partner) with testing showing there is no sperm in the semen;
bilateral tubal ligation or occlusion; or intrauterine device. Acceptable methods of birth control for men include sexual abstinence (refraining from heterosexual intercourse); vasectomy with testing showing there is no sperm in the semen; bilateral tubal ligation or occlusion in the partner; or a condom (the female partner should also consider a form of birth control).
Combination Therapy (pembrolizumab plus AMG 510): WOBCP who are unwilling to practice the above-mentioned highly effective methods of birth control during treatment with pembrolizumab plus AMG 510 and for at least 4 months after receiving the last dose of any study drug.
16. Women who are lactating/breast feeding or who plan to breastfeed while on study through 7 days (or 4 months if receiving combination therapy with pembrolizumab) after receiving the last dose of study drug.
17. Women with a positive pregnancy test.
18. Women planning to become pregnant while on study through 7 days (or 4 months if receiving combination therapy with pembrolizumab) after receiving the last dose of study drug
19. Subject has known sensitivity to any of the products to be administered during dosing
20. Subject will not be available for protocol-required study visits or procedures, to the best of the subject and investigator’s knowledge
21. Subject has any kind of disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or to comply with all required study procedures
22. History or evidence of any other clinically significant disorder, that would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
23. Use of known cytochrome P450 (CYP) 3A4 and MATE1 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
24. 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
25. History of other malignancy within the past 2 years
26. Previous treatment with a direct KRASG12C inhibitor
- Dose Comparison Study (Phase 2 Part B) – Specific Exclusion Criteria
27. Use of known P-gp sensitive substrates (with a narrow therapeutic window), within 14 days or 5 half-lives of the drug or its major active metabolite, prior to study day 1.
28. Use of proton-pump inhibitors (PPIs) or H2 receptor antagonists within 14 days or 5 half-lives of the drug or its major active metabolite, prior to study day 1
See protocol for additional detail on exclusion criterion |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1
Part 1a/2a
Incidence of treatment-emergent adverse events, treatment-related adverse events, and clinically significant changes in vital signs, physical examinations, electrocardiograms (ECGs), and clinical laboratory tests
Subject incidence of dose-limiting toxicity (DLT)
Part 1b/2b and 1d/2d
Incidence of DLTs, treatment-emergent adverse events, treatment-related adverse events, and changes in vital signs, ECGs, and clinical laboratory tests
Part 1c/2c
Incidence of DLTs, treatment-emergent adverse events, treatment-related adverse events, and clinically significant changes in vital signs, physical examinations, ECGs, and clinical laboratory tests
Part 2e
Incidence of DLTs, treatment-emergent adverse events, treatment-related adverse events, and changes in vital signs, ECGs, and clinical laboratory tests
Objective response (OR = complete response [CR] + partial response [PR]), duration of response (DOR), disease control (CR + PR + stable disease [SD]), progression-free survival (PFS), duration of stable disease, and time to response (TTR) measured by computed tomography (CT) or magnetic resonance imaging (MRI) and assessed per RECIST 1.1. Response will be assessed by blinded independent central review (BICR). Complete response and partial response (PR) require confirmatory CT or MRI repeat assessment at least 4 weeks after the first detection of response.
Phase 2
Part A
Objective response (ORR = CR + PR), measured by CT or MRI and assessed per RECIST 1.1. Response will be assessed by BICR. Complete response and PR require confirmatory CT or MRI repeat assessment at least 4 weeks after the first detection of response.
Part B
Objective response (ORR = CR + PR), measured by CT or MRI and assessed per RECIST 1.1. Response will be assessed by blinded independent central review (BICR). Complete response and PR require confirmatory CT or MRI repeat assessment at least 4 weeks after the first detection of response.
Treatment emergent adverse events (TEAE), grade ≥3 TEAE, serious adverse event (SAEs), and events of interest (EOIs) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety data will be reviewed on an ongoing basis by Amgen.
Phase 2 Part A
The primary analysis will occur when either 105 NSCLC or 60 CRC evaluable subjects enrolled in the phase 2 are treated at the monotherapy RP2D and have 6-months follow-up time, whichever occurs first (NSCLC or CRC).
Phase 2 Part B
The primary analysis for phase 2 Part B is planned approximately 6 months after last subject enrolled in phase 2 Part B.
The final analysis will occur when the end of study as described in the protocol Section 3.4.2 has been reached. The data will be analyzed once they have been entered, cleaned, and locked. The purpose of this analysis is to summarize efficacy and safety after all subjects have complete follow-up. |
|
| E.5.2 | Secondary end point(s) |
Phase 1
Part 1a/2a, 1b/2b, 1d/2d
PK parameters of AMG 510 including, but not limited to, maximum plasma concentration (Cmax), time to achieve Cmax (tmax), and area under the plasma concentration-time curve (AUC)
OR, DOR, disease control, PFS, duration of stable disease, and TTR measured by CT or MRI and assessed per RECIST 1.1. Response will be assessed by BICR. Complete response and PR require confirmatory CT or MRI repeat assessment at least 4 weeks after the first detection of response.
Overall Survival (OS)
PK parameters of AMG 510 including, but not limited to, Cmax, tmax, and AUC in the fed and/or fasted state
AMG 510 exposure/QTc interval relationship
Part 1c/2c
PK parameters of AMG 510 including, but not limited to, Cmax, tmax, and AUC
OR, DOR, disease control, PFS, duration of stable disease, and TTR measured by CT or MRI and assessed per RECIST 1.1. Response will be assessed by BICR. Complete response and PR require confirmatory CT or MRI repeat assessment at least 4 weeks after the first detection of response.
OS
Part 2e
PK parameters of AMG 510 including, but not limited to Cmax, tmax, and AUC
PK parameters for midazolam including, but not limited to: Cmax, AUC, clearance, and t1/2
Phase 2 Part A
- Duration of response (DOR)
- Disease control rate (DCR)
- Time to response (TTR)
- Progression-free survival (PFS)
- Overall survival (OS)
- 6-month PFS and 12 month PFS
- 12-month OS
Incidence and severity of adverse events
PK parameters of AMG 510 including, but not limited to, Cmax, tmax, and AUC.
Part B
- Duration of response (DOR)
- Disease control (DCR = CR + PR + SD)
- Depth of response (best percent change from baseline in lesion sum diameters)
- Time to response (TTR)
- Progression free survival (PFS)
- Overall survival (OS)
PK parameters of AMG 510 including, but not limited to, Cmax and AUC
Changes in cancer-specific symptoms and overall health status using subject reported outcome instruments:
- Impact of treatment on disease related symptoms and HRQOL (instruments; EORTC QLQ C30 + disease-specific modules QLQ LC13 and NSCLC SAQ for NSCLC; PGIS and PGIC in cough, dyspnea and chest pain among NSCLC patients)
- Treatment-related symptoms and impact on the subject (EORTC QLQ C30, selected questions from the PRO-CTCAE library and a single item about symptom bother, item GP5 of the FACT-G)
Physical function (instrument: EORTC QLQ-C30, Physical function scale) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 2 Part A
The primary analysis will occur when either 105 NSCLC or 60 CRC evaluable subjects enrolled in the phase 2 are treated at the monotherapy RP2D and have 6-months follow-up time, whichever occurs first (NSCLC or CRC).
Phase 2 Part B
The primary analysis for phase 2 Part B is planned approximately 6 months after last subject enrolled in phase 2 Part B.
The final analysis will occur when the end of study as described in the protocol Section 3.4.2 has been reached. The data will be analyzed once they have been entered, cleaned, and locked. The purpose of this analysis is to summarize efficacy and safety after all
subjects have complete follow-up. |
|
| 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 | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 7 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 61 |
| 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 |
| Australia |
| Brazil |
| Canada |
| China |
| Japan |
| Korea, Republic of |
| United States |
| Austria |
| Belgium |
| France |
| Germany |
| Switzerland |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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, long-term follow-up), as applicable. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 24 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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