​​Sotorasib and Panitumumab Versus Investigator’s Choice for Subjects with KRAS p.G12C Mutation (CodeBreaK 300)​

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Amgen Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

28 Mar 2022 → 15 Apr 2026

Decision date (initial)

2024-10-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Amgen Inc.

External identifiers

EU CT number

2024-511187-81-00

EudraCT number

2021-004008-16

WHO UTN

U1111-1309-4984

ClinicalTrials.gov

NCT05198934

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Pharmacokinetic, Safety

​To compare progressionfree survival (PFS) in previously treated subjects with KRAS p.G12C mutated colorectal cancer (CRC) receiving sotorasib 240 mg once daily (QD) and panitumumab vs investigator’s choice (trifluridine and tipiracil or regorafenib), and sotorasib 960 mg QD and panitumumab vs investigator’s choice (trifluridine and tipiracil or regorafenib)

Secondary objectives 7

1. ​To compare overall survival (OS) in previously treated subjects with KRAS p.G12C mutated CRC receiving sotorasib 240 mg QD and panitumumab vs investigator’s choice (trifluridine and tipiracil or regorafenib), and sotorasib 960 mg QD and panitumumab vs investigator’s choice (trifluridine and tipiracil or regorafenib)
2. To evaluate efficacy of sotorasib 240 mg QD and panitumumab vs investigator’s choice (trifluridine and tipiracil or regorafenib), and sotorasib 960 mg QD and panitumumab vs investigator’s choice (trifluridine and tipiracil or regorafenib), as assessed by:   Objective response rate (ORR)
3. ​To evaluate efficacy of sotorasib 240 mg QD and panitumumab vs investigator’s choice (trifluridine and tipiracil or regorafenib), and sotorasib 960 mg QD and panitumumab vs investigator’s choice (trifluridine and tipiracil or regorafenib), as assessed by:   Duration of response (DOR) Time to response (TTR) Disease control rate (DCR) Investigator assessed ORR and PFS
4. ​To evaluate the safety and tolerability of sotorasib 240 mg QD and panitumumab vs investigator’s choice (trifluridine and tipiracil or regorafenib), and sotorasib 960 mg QD and panitumumab vs investigator’s choice (trifluridine and tipiracil or regorafenib)
5. To evaluate the impact of sotorasib 240 mg QD and panitumumab vs investigator's choice (trifluridine and tipiracil or regorafenib) and sotorasib 960 mg QD and panitumumab vs investigator’s choice (trifluridine and tipiracil or regorafenib) on patientreported fatigue, pain, physical function, and global health status (patient reported outcomes [PRO]
6. ​To evaluate and compare the effect of treatment with sotorasib 240 mg and panitumumab vs investigator's choice (trifluridine and tipiracil or regorafenib), and sotorasib 960 mg QD and panitumumab vs investigator’s choice (trifluridine and tipiracil or regorafenib) on other treatment and disease related symptoms and health related quality of life relative to investigator’s choice (trifluridine and tipiracil or regorafenib)
7. ​To characterize the pharmacokinetics (PK) of sotorasib and panitumumab

Conditions and MedDRA coding

Colorectal Cancer (CRC)

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Subject has provided informed consent/assent prior to initiation of any study specific activities/procedures.
2. Age ≥ 18 years.
3. Pathologically documented metastatic colorectal adenocarcinoma with KRAS p.G12C mutation as determined by prospective central testing, using the analytically validated Qiagen Therascreen KRAS RGQ polymerase chain reaction (PCR) kit in CRC as an investigational device demonstrating a KRAS p.G12C mutation is present. Local testing and documentation of KRAS p.G12C mutation should have been previously performed as part of standard of care.
4. Subjects will have received at least 1 prior line of therapy for metastatic disease. Subjects must have received and progressed or experienced disease recurrence on or after fluoropyrimidine, irinotecan, and oxaliplatin given for metastatic disease unless the subject, in the opinion of the investigator, is not a candidate for fluoropyrimidine, irinotecan, or oxaliplatin, in which case, the subject may be eligible after investigator discussion with Amgen medical monitor provided subject has received at least one prior line of therapy for metastatic disease and provided trifluridine and tipiracil or regorafenib is deemed the appropriate next line of therapy for the subject. Notes: Subjects with tumors known to be MSI-H must have received prior checkpoint inhibitor therapy if available in the region unless there is a medical contraindication, in which case, the subject may be eligible after investigator discussion with Amgen medical monitor. Subjects with tumors known to have BRAF V600E mutation must have received prior treatment with encorafenib and cetuximab if available for this indication in the country or region unless there is a medical contraindication in the opinion of the investigator, in which case the subject may be eligible for the trial after investigator discussion with and approval of the Amgen medical monitor.  Adjuvant therapy will count as a line of therapy for metastatic disease if the subject progressed on or within six months of completion of adjuvant therapy administration.  Maintenance therapy is not considered as a separate regimen of therapy.  Adjuvant therapy given after resection of metastatic disease counts as a line of therapy for metastatic disease. Perioperative chemotherapy with or without chemoradiation in the metastatic setting will count as one line of therapy for metastatic disease if that was part of a multidisciplinary treatment plan for surgery.
5. Subjects must be willing to provide archived tumor tissue samples (formalin-fixed paraffin-embedded [FFPE] sample collected within 5 years) or agree to undergo a pretreatment tumor biopsy (excisional or core biopsy) prior to enrollment.
6. Measurable disease per RECIST 1.1 criteria. Lesions previously radiated are not considered measurable unless they have progressed after radiation.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2
8. Life expectancy of > 3 months, in the opinion of the investigator
9. Adequate hematologic and end-organ function, defined as the following within 2 weeks prior to cycle 1 day 1:  Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L (without granulocyte colony-stimulating factor support within 2 weeks of laboratory test used to determine eligibility)  Hemoglobin ≥ 9.0 g/dL (without transfusion within 2 weeks of laboratory test used to determine eligibility)  Platelet count ≥ 100 x 109 /L (without transfusion within 2 weeks of laboratory test used to determine eligibility)  Aspartate aminotransferase (AST) and ALT ≤ 2.5 times the upper limit of normal (ULN)  Serum bilirubin ≤ 1.0 x ULN. For subjects with Gilbert’s disease, total bilirubin or direct bilirubin needs to be ≤ 1.0 x ULN  International normalized ratio (INR) and activated partial thromboplastin time (or partial thromboplastin time) ≤ 1.5 x ULN. Prothrombin time (PT) ≤ 1.5 x ULN may be used instead of INR for sites whose labs do not report INR  Estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation ≥ 30 mL/min/1.73 m2
10. Fridericia's Correction Formula (QTcF) ≤ 470 msec
11. Ability to take oral medications and willing to record daily adherence to investigational product.

Exclusion criteria 24

1. Active brain metastases. Subjects who have had brain metastases resected or have received radiation therapy ending at least 4 weeks prior to study day 1 are eligible
2. History or presence of hematological malignancies unless curatively treated with no evidence of disease 2 years
3. History of other malignancy within the past 3 years, with exceptions specified in the protocol
4. Leptomeningeal disease
5. Significant GI disorder that results in significant malabsorption, requirement for IV alimentation, or inability to take oral medication
6. History of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial pneumonitis or pulmonary fibrosis
7. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 6 months prior to randomization, unstable arrhythmias or unstable angina
8. Significant uncontrolled concomitant disease that could affect compliance with protocol procedures or interpretation of results or that pose a risk to subject safety
9. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures at a frequency greater than monthly.
10. Known history of human immunodeficiency virus infection
11. Exclusion of hepatitis infection based on the following results and/or criteria: a)Positive hepatitis B surface antigen b)Negative HepBsAg with a positive for hepatitis B core antibody 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
12. Subjects have received both trifluridine and tipiracil and regorafenib in the past
13. Unresolved toxicities from prior anti-tumor therapy
14. Previous treatment with a KRAS G12C inhibitor
15. Prior treatment with trifluridine and tipiracil in those subjects where investigator's choice would be trifluridine and tipiracil
16. Prior treatment with regorafenib in those subjects where investigator's choice would be regorafenib
17. Therapeutic or palliative radiation therapy within 2 weeks of study day 1
18. Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy [except for subjects with history of completely resected breast cancer with no active disease for over 3 years on long term adjuvant endocrine therapy], or investigational agent) within 4 weeks of study day 1; please note that bisphosphonates or anti-RANKL antibody therapy is allowed if needed for management of hypercalcemia or for prevention of skeletal events. Checkpoint inhibitor therapy within 6 weeks of study day 1 is also excluded
19. Required dose reduction of panitumumab in the past for toxicity
20. Use of warfarin. Other anticoagulation may be allowed
21. Use of known cytochrome P450 (CYP) 3A4 sensitive substrates and P-glycoprotein (P-gp) 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
22. Use of strong inducers of CYP3A4 within 14 days or 5 half-lives prior to study day 1
23. Where Investigator's choice is regorafenib: use of strong inhibitors of CYP3A4 (including herbal supplements such as Goldenseal) within 14 days or 5 half-lives (whichever is longer) or grapefruit juice or grapefruit containing products within 7 days prior to study day 1
24. Therapeutic oral or IV antibiotics within 2 weeks prior to randomization

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. ​PFS – defined as time from randomization until disease progression or death from any cause, whichever occurs first, for all subjects.  Progression will be assessed using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) per Blinded Independent Central Review (BICR)

Secondary endpoints 7

1. ​Overall survival - defined as time from randomization until death from any cause
2. Objective response = complete response (CR) + partial response (PR), assessed per RECIST 1.1.  Response will be assessed by BICR.  CR and PR require confirmatory repeat assessment at least 4 weeks after the first detection of response
3. ​Incidence and severity of treatmentemergent adverse events, changes in vital signs, and changes in clinical laboratory tests
4. ​Change from baseline over time to week 8   Fatigue severity measured by item 3 on the brief faigure invetory
5. ​Pharmacokinetic (PK) parameters of sotorasib and panitumumab including, but not limited to, maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC)
6. Change from baseline over time to 8 weeks for the BFI, BPI and EORTC QLQ-C30. Summary scores and changes from baseline of VAS scores as measured by EuroQol-5D level 5. Summary scores on symptom bother on GP5 from FACT-G. Summary scores of Patient Global Impression of change at each timepoint.
7. ​Duration of overall response - defined as time from first evidence of PR or CR to disease progression or death due to any cause, whichever occurs first.  Progression will be based on BICR per RECIST 1.1

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Comparator 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Amgen Inc.

Sponsor organisation

Amgen Inc.

Address

1 Amgen Center Drive

City

Thousand Oaks

Postcode

91320-1730

Country

United States

Scientific contact point

Organisation

Amgen Inc.

Contact name

Medical Information

Public contact point

Organisation

Amgen Inc.

Contact name

Medical Information

Third parties 12

Locations

5 EU/EEA countries · 21 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 78 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications