Neoplasms

Digestive System Diseases

All Conditions

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Capecitabine

Antimetabolites

* Regorafenib dose level 1-3: day 1 to 14 and day 22 to 35 (2 weeks on 1 week off, 2 weeks on, including Saturday and Sunday) at a daily dose according to the escalation table.
* Regorafenib dose level -1: day 1 to 5, day 8 to 12, day 22 to 26 and day 29 to 33 (5 days on and 2 days off during week 1, 2, 4 and 5; week 3 off) at a daily dose according to the escalation table.
* Capecitabine: day 1 to 38 (5 weeks and 3 days, including Saturday and Sunday) according to dose escalation table. The intake stops in the evening of the last day of RT.
* External beam Radiotherapy
* Surgery

* Regorafenib dosel level 1-3: day 1 to 14 and day 22 to 35 (2 weeks on 1 week off, 2 weeks on, including Saturday and Sunday) at a daily dose according to the escalation table.
* Regorafenib dosel level -1: day 1 to 5, day 8 to 12, day 22 to 26 and day 29 to 33 (5 days on and 2 days off during week 1, 2, 4 and 5; week 3 off) at a daily dose according to the escalation table.

Regorafenib

• Capecitabine: day 1 to 38 (5 weeks and 3 days, including Saturday and Sunday) according to dose escalation table. The intake stops in the evening of the last day of RT.

Monday through Friday for 5 weeks and 3 days (d1-38) starting on day 1 (daily fraction 1.8 Gy, final dose 50.4 Gy).

Radiotherapy

6-12 weeks (± 1 week) after radio-chemotherapy (RCT) has been completed (42-84 days after last day of RCT).

Surgery

Sara Bastian, MD

Despite treatment of locally advanced rectal cancer relapses are frequent. Several attempts to improve these results with therapy intensification have shown modest effect on disease free survival (DFS) and overall survival (OS). Recent studies with addition of sorafenib and cediranib revealed promising effect on tumor response with acceptable toxicity. Regorafenib is a multi tyrosine kinase inhibitor (TKI) with a broad mechanism of action. Therefore this trial investigates if similar results can be achieved as with sorafenib or cediranib.

Despite treatment of locally advanced rectal cancer relapses are frequent. Several attempts to improve these results with therapy intensification have shown modest effect on disease free survival (DFS) and overall survival (OS). Recent studies with addition of sorafenib and cediranib revealed promising effect on tumor response with acceptable toxicity. Regorafenib is a multi tyrosine kinase inhibitor (TKI) with a broad mechanism of action. Therefore this trial investigates if similar results can be achieved as with sorafenib or cediranib.

The objective of the dose escalation part is to determinate safety, tolerability and the recommended dose. The objective of the expansion cohort is to assess the efficacy and to further characterize safety and tolerability of the therapy.

Neoadjuvant Treatment With Regorafenib and Capecitabine Combined With Radiotherapy in Locally Advanced Rectal Cancer

Neoadjuvant Treatment With Regorafenib and Capecitabine Combined With Radiotherapy in Locally Advanced Rectal Cancer. A Multicenter Phase Ib Trial (RECAP)

In the dose escalation part the dose limiting toxicity (DLTs) is observed during and up to 4 weeks after the last administration of RCT.

In the dose escalation part the pathological near complete or complete tumor response (npCR or pCR) is specified.

Quality of the mesorectal excision including details of the circumferential resection margin (CRM)/surface according to Nagtegaal.

Sphincter preservation is defined as preservation of the rectal sphincter or part of it.

Dworak tumor regression grading (TRG) system.

Negative (clear) circumferential margins are defined by an invasion front which is at a \> 1mm distance from the lateral resection margin; circumferential resection margins of ≤ 1 mm are considered positive (involved).

CRM negative (clear) ≤ 1mm and CRM positive (involved) ≤ 1mm.

Downstaging of primary tumor and/or lymph nodes (comparison between mrT/N and ypT/N)

Surgical complications within 8 weeks after surgery. A surgical local complication is defined as either:

* insufficiency of anastomosis
* fistula
* severe local infection requiring antibiotics
* bladder dysfunction
* erectile dysfunction
* additional interventions / operation needed (e.g. drainage of hematoma/abscess)

Swiss Group for Clinical Cancer Research

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Micronutrients

Hematinics

Vitamins

Pemetrexed

Cisplatin

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Folinic Acid

Folate

Vitamin B9

The trial consists of two parts:

* Part 1: dose escalation based on the 3+3 design with 2 doses of binimetinib
* Part 2: expansion cohort at the recommended maximum tolerated dose (MTD) level of binimetinib

Binimetinib will be administered in combination with pemetrexed and cisplatin (induction therapy), and with pemetrexed only (maintenance therapy), during the first 2 weeks of each cycle. Cycles will be repeated every 21 days.

Binimetinib

Pemetrexed 500 mg/m2 i.v. is applied on day 1 of each cycle, before cisplatin administration

Cisplatin 75 mg/m2 i.v. is applied on day 1 of each induction therapy cycle. The drug must be administered after pemetrexed infusion

Martin Früh, MD

The aim is to determine the recommended phase 2 dose (RP2D) of binimetinib in combination with pemetrexed and cisplatin, and to demonstrate that the combination is feasible and has preliminary activity in previously untreated patients with advanced NSCLC and documented KRAS mutations.

There is a need for more effective therapies for patients with advanced NSCLC driven by the RAS/MEK/ERK pathway. These tumors are generally aggressive, are almost exclusively of non-squamous histology, and represent the largest group of patients with advanced NSCLC harboring specific driver mutations in Western populations.

Based on recent preclinical and clinical evidence, mitogen-activated protein kinase kinase (MEK)-inhibition plus first-line chemotherapy is a promising new treatment for patients with NSCLC and KRAS \[v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog\] mutations.

Binimetinib is a medication without marketing authorization. Pemetrexed and cisplatin have marketing authorization in Switzerland and in EU for the treatment of non-small cell lung cancer (NSCLC) and will be administered as standard backbone treatment according to their Swissmedic-approved indication, dose and route of administration. Binimetinib, pemetrexed and cisplatin are IMP in the context of this phase I trial.

Binimetinib in Addition to Standard Chemotherapy in KRAS Mutated NSCLC.

Binimetinib, Pemetrexed and Cisplatin, Followed by Maintenance With Binimetinib and Pemetrexed, in Patients With Advanced Non-small Cell Lung Cancer NSCLC With KRAS Mutations. A Multicenter Phase IB Trial.

A DLT is defined as an AE or abnormal laboratory value assessed as at least possibly related to trial treatment (binimetinib in combination with pemetrexed and cisplatin), which occurs ≤ 21 days following the first dose of trial treatment during cycle 1.

OR will include complete and partial responses based on RECIST 1.1 criteria. Best response will be the best result by investigator and RECIST 1.1 in the planned follow-up CT scans.

PFS will be calculated from registration until documented tumor progression according to RECIST 1.1 or death due to any reason, whichever occurs first.

OS will be calculated from registration until death due to any reason.

AEs will be assessed according to NCI CTCAE V.4.03.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Neoadjuvant Treatment With Regorafenib and Capecitabine Combined With Radiotherapy in Locally Advanced Rectal Cancer	NCT02910843	Rectal Cancer	Regorafenib Capecitabine Radiotherapy Surgery	18 Years - 75 Years	Swiss Group for Clinical Cancer Research
Binimetinib in Addition to Standard Chemotherapy in KRAS Mutated NSCLC.	NCT02964689	Advanced Non-sm... KRAS Gene Mutat... Lung Cancer	Binimetinib Pemetrexed Cisplatin	18 Years - 75 Years	Swiss Group for Clinical Cancer Research
Neoadjuvant Treatment With Regorafenib and Capecitabine Combined With Radiotherapy in Locally Advanced Rectal Cancer	NCT02910843	Rectal Cancer	Regorafenib Capecitabine Radiotherapy Surgery	18 Years - 75 Years	Swiss Group for Clinical Cancer Research
Binimetinib in Addition to Standard Chemotherapy in KRAS Mutated NSCLC.	NCT02964689	Advanced Non-sm... KRAS Gene Mutat... Lung Cancer	Binimetinib Pemetrexed Cisplatin	18 Years - 75 Years	Swiss Group for Clinical Cancer Research

Spots Global Cancer Trial Database for phase ib trial