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Antineoplastic Agents

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Pharmaceutical Solutions

Irinotecan

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Part C: Combination therapy expansion part

BI 1701963

Camptosar®

This study is open to adults with advanced bowel cancer (colorectal cancer) with a KRAS mutation. This is a study in people for whom previous treatment was not successful and surgery is not a treatment option.

The purpose of this study is to find the highest dose of BI 1701963 that people with bowel cancer can tolerate when taken together with a medicine called irinotecan. The study also tests whether BI 1701963 in combination with irinotecan is able to make tumours shrink. BI 1701963 may help to turn off KRAS. Activating KRAS mutations make tumours grow. Irinotecan is a medicine to treat bowel cancer.

Participants can stay in the study as long as they benefit from treatment and can tolerate it.

During this time, participants take BI 1701963 as tablet once a day and get irinotecan as infusion every two weeks. The doctors regularly monitor the size of the tumour. The doctors also collect information on any health problems of the participants.

Trial consists of three parts: Monotherapy safety run-in part (Part A), combination dose escalation part (Part B), combination therapy expansion part (Part C). A randomization will be included for the expansion therapy part (Part C) because the same patient population will be recruited to two different dose levels at the same time.

A Study to Test Different Doses of BI 1701963 in Combination With Irinotecan in People With Advanced Bowel Cancer With Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) Mutation

A Phase 1 Open-label Dose Escalation Trial of BI 1701963 in Combination With Irinotecan in KRAS Mutation Positive Patients With Unresectable Locally Advanced or Metastatic Colorectal Cancer

Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents, except for the following exclusions:

1. studies in products where Boehringer Ingelheim is not the license holder; 2. studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials; 3. studies conducted in a single center or targeting rare diseases (because of limitations with anonymization).

For more details refer to: https://www.mystudywindow.com/msw/datasharing

Combination dose escalation part (Part B)

Combination therapy expansion part (Part C)

Monotherapy safety run-in and combination dose escalation part (Part A+B)

Boehringer Ingelheim

Bevacizumab

Fluorouracil

Tin Fluorides

Oxaliplatin

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Lead in Treatment Period

* Will consist of 6 cycles of Bevacizumab® + mFOLFOX6
* Each cycle length is 14 days

After completion of the Lead-in Period, patients who have not progressed or experienced intolerable side effects and remain on study will be randomized 1:1 to either the Non-Switch or Switch Arm of the study.

Switch Arm

* TRS003, 5 mg/kg IV every 14 days with mFOLFOX6 for 1 cycle followed by switch to:
* Bevacizumab®, 5 mg/kg IV every 14 days with mFOLFOX6 for 1 cycle followed by switch to:
* TRS003, 5 mg/kg IV every 14 days with mFOLFOX6 until end of treatment due to PD, intolerability or other cause for stopping treatment. Intensive PK sampling will be performed after 7 cycles of this TRS003 switch period (to occur during Cycle 14, adequate for washout of preceding Bevacizumab®).

Lead in Treatment Period

* Will consist of 6 cycles of Bevacizumab® + mFOLFOX6
* Each cycle length is 14 days After completion of the Lead-in Period, patients who have not progressed or experienced intolerable side effects and remain on study will be randomized 1:1 to either the Non-Switch or Switch Arm of the study.

Non-Switch Arm:

* Bevacizumab®, 5 mg/kg administered IV every 14 days
* mFOLFOX6 administered as described above every 14 days

* TRS003, 5 mg/kg IV every 14 days with mFOLFOX6 for 1 cycle followed by switch to:
* Bevacizumab®, 5 mg/kg IV every 14 days with mFOLFOX6 for 1 cycle followed by switch to:
* TRS003, 5 mg/kg IV every 14 days with mFOLFOX6 until end of treatment due to PD, intolerability or other cause for stopping treatment. Intensive PK sampling will be performed after 7 cycles of this TRS003 switch period

TRS003

• Bevacizumab®, 5 mg/kg IV every 14 days with mFOLFOX6 for 1 cycle

China-approved Bevacizumab

The mFOLFOX6 regimen is:

* Oxaliplatin, 85 mg/m2 administered IV over 2 hours
* LCV, 400 mg/m2 administered over 2 hours concurrent with oxaliplatin
* 5-FU, 400 mg/m2 given as a slow IV push (bolus) over 5 minutes administered immediately after LCV
* 5-FU, 2400 mg/m2 administered IV over 46 hours by infusion pump beginning immediately after FU IV bolus.

mFOLFOX6

Hongwei Kang

This is a Phase 3, multicenter, randomized and double-blind study assessing the interchangeability between TRS003 and China-approved Bevacizumab® (also called China-approved Avastin) for first-line treatment of patients with metastatic Colorectal Cancer (CRC), approximately 126 patients will be enrolled in this study. Patients who sign the informed consent, meet the eligibility criteria and are confirmed as non-progressors after lead-in treatment period with Bevacizumab® in combination with modified FOLFOX6 chemotherapy for 6 cycles, will be randomized (1:1) to either the non-switching arm and receive Bevacizumab® + modified FOLFOX6 for all subsequent cycles or to the switching arm and receive TRS003 alternating with Bevacizumab® in combination with mFOLFOX6 until disease progression or intolerability.

This is a randomized, double-blind Phase 3 clinical trial evaluating the interchangeability, by a comparison of PK parameters between non-Switching and the Switching arms following the final switch between TRS003 and Bevacizumab® in patients with metastatic adenocarcinoma of the colon or rectum (please note that Bevacizumab® means China-approved Bevacizumab® in this protocol, unless otherwise specified). Approximately 126 patients will be enrolled in this study. Patients who sign the informed consent, meet the eligibility criteria and are confirmed as non-progressors after lead-in treatment period with Bevacizumab® in combination with modified FOLFOX6 chemotherapy for 6 cycles, will be randomized (1:1) to either the non-switching arm and receive Bevacizumab® + modified FOLFOX6 for all subsequent cycles or to the switching arm and receive TRS003 alternating with Bevacizumab® in combination with mFOLFOX6 until disease progression or intolerability. There will be 3 switches as detailed in the Treatment section (below) and the Schema. If oxaliplatin-induced neurotoxicity requires discontinuation of oxaliplatin, treatment will continue using leucovorin (LCV) plus 5-fluorouracil (5-FU) in combination with either Bevacizumab® or TRS003 until progressive disease (PD), intolerability, or other cause for stopping treatment.

A Phase 3, Multicenter, Randomized and Double-blind Study Assessing the Interchangeability between TRS003 and China-approved Bevacizumab® (also called China-approved Avastin) For First-Line Treatment of Patients with Metastatic Colorectal Cancer (CRC)

This is a double-blind study. Neither the subjects, nor the Investigator, nor the Sponsor knows which drug is being administered to which group. Only the Biostatistician who generated the actual randomization scheme with IWRS and the Pharmacist or nurse at the study center who prepares the study drugs and dose for the subjects will be unblinded. All other study related individuals including ancillary clinical staff, biological laboratory staff, clinical research associates, medical monitors, and scientific operation and management team at the study center will remain blinded to the treatment assignment.

A Study Assessing the Interchangeability Between TRS003 and Bevacizumab® For CRC

A Phase 3, Multicenter, Randomized and Double-blind Study Assessing the Interchangeability Between TRS003 and China-approved Bevacizumab® (Also Called China-approved Avastin) For First-Line Treatment of Patients With Metastatic Colorectal Cancer (CRC)

The natural log-transformed AUCtau in Cycle 14 will be analyzed.

Besides AUCtau, the PK parameters to be estimated will include the trough concentration (Ctrough), the maximum concentration (Cmax), and time to reach Cmax (Tmax).

anti-drug antibody (ADA) and neutralizing antibody if ADA is positive

Progression-free survival (PFS) is defined as the time from randomization to Investigator-determined PD or death due to any cause in the absence of documented PD.

Overall survival (OS) is defined as the time from randomization to death due to any cause.

ORR in the TRS003 Arm/ORR in the China-approved bevacizumab Arm Confidence interval of ORR in each group will be estimated by the Clopper-Pearson Exact method.

Duration of response (DOR) is defined as the time from the date of the first documentation of Investigator-determined response in patients with confirmed objective tumor response (CR or PR) to the first documentation of Investigator determined disease progression (PD) or to death due to any cause in the absence of documented PD.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study to Test Different Doses of BI 1701963 in Combination With Irinotecan in People With Advanced Bowel Cancer With Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) Mutation	NCT04627142	Metastatic Colo...	BI 1701963 Camptosar®	18 Years -	Boehringer Ingelheim
A Study Assessing the Interchangeability Between TRS003 and Bevacizumab® For CRC	NCT05378867	Metastatic Colo...	TRS003 China-approved ... mFOLFOX6	18 Years -	Zhejiang Teruisi Pharmaceutical Inc.
A Study Assessing the Interchangeability Between TRS003 and Bevacizumab® For CRC	NCT05378867	Metastatic Colo...	TRS003 China-approved ... mFOLFOX6	18 Years -	Zhejiang Teruisi Pharmaceutical Inc.

Spots Global Cancer Trial Database for metastatic colorectal cancer (crc)