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Carcinoma, Non-Small-Cell Lung

Carcinoma

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Carcinoma, Bronchogenic

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Paclitaxel

Carboplatin

Pemetrexed

Albumin-Bound Paclitaxel

Immunomodulating Agents

Tubulin Modulators

Antimitotic Agents

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Folinic Acid

Folate

Vitamin B9

3 cycles of neoadjuvant Toripalimab (240mg every 3 weeks) with nab-paclitaxel + carboplatin, or pemetrexed + carboplatin (decided by investigators; nab-paclitaxel 135 mg/m2, d1, 8 and carboplatin AUC 5, d1 every 3 weeks; pemetrexed, 500mg/m2 d1 every 3 weeks) will be administered before surgery, followed by optional adjuvant treatment including chemotherapy for 3-4 cycles or rare mutations-TKIs for up to 2 years or till disease progression or unacceptable toxicity.

Toripalimab

Nab paclitaxel

Wen-Zhao Zhong, Ph.D

Rui Fu, Ph.D

Chao Zhang, Ph.D

Phase II, single-arm, open-label single center study that assess clinical feasibility and safety of 3 cycles neoadjuvant Toripalimab plus chemotherapy in rare mutations stage IIB-IIIB NSCLC followed by optional adjuvant treatment upon investigators' decisions.

30 eligible patients will be enrolled and 3 cycles of Toripalimab 240mg + chemotherapy (Nab-paclitaxel + carboplatin, or pemetrexed + carboplatin) will be administered. Rare mutations include RET fusions, BRAF (V600E or non-V600E but confirmed driver mutations), ERBB2 exon20 insertion, MET amplification (FISH confirmed) or exon 14 skipping. Dynamic blood samples before, during or after neoadjuvant treatment will be obtained for exploratory analysis. Patients who showed inferior response to neoadjuvant treatment leading to unresectable disease will be scheduled for local radiation or other potential subsequent treatment regarding multidisciplinary discussion. After completion of local treatment (surgery or radiation), patients will be provided with optional adjuvant treatment including chemotherapy or/and rare mutations TKI upon investigators' consideration. The primary objective of the study is pathological complete response (pCR) defined as no residue tumor found in both primary lung cancer and metastatic lymph nodes.

3 cycles of neoadjuvant Toripalimab (240mg every 3 weeks) with nab-paclitaxel + carboplatin, or pemetrexed + carboplatin (decided by investigators; nab-paclitaxel 135 mg/m2, d1, 8 and carboplatin AUC 5, d1 every 3 weeks; pemetrexed, 500mg/m2 d1 every 3 weeks) will be administered before surgery, followed by optional adjuvant treatment including chemotherapy for 3-4 cycles or rare mutations-TKIs for up to 2 year or till disease progression or unacceptable toxicity.

Neoadjuvant Immunotherapy in Rare Mutations Localized NSCLC

Neoadjuvant Toripalimab Combined With Chemotherapy in Rare Mutations Stage IIB-IIIB NSCLC

Evaluation of the pathological complete response: The pathological complete response is defined as the absence of residual tumor in both lung and lymph nodes after neoadjuvant treatment.

Percentage of Participants with Major Pathologic Response. MPR was defined as percentage of tumor cells within tumor bed less than 10% for both primary lung lesions and metastatic lymph nodes.

Event-free survival (EFS) is defined as the length of time from initiation of neoadjuvant treatment to any of the following events: any progression of disease precluding surgery, progression or recurrence disease based on response evaluation criteria in solid tumors (RECIST) 1.1 after surgery, or death due to any cause.

Overall survival (OS) is defined as the time between the date of initiation of neoadjuvant treatment and the date of death.

Incidence of all grade AE which has been confirmed to be correlated with neoadjuvant treatment or surgery.

Shanghai Junshi Bioscience Co., Ltd.

Guangdong Provincial People's Hospital

Symptoms and General Pathology

Neoplasm Metastasis

Antirheumatic Agents

Dermatologic Agents

Reproductive Control Agents

Methotrexate

Tepotinib

Tepotinib 500mg (2 tablets of 250mg) per day D1-21 orally, once daily

Ki Hyeong Lee, M.D.

Eun Joo Kang, M.D.

Soon Il Lee

Yu Jeong Kim

Yun Ji Choe

The aim of this study is to understand efficacy of tepotinib in patients with solid cancers harbouring c-MET amplification or exon 14 mutation who progressed after standard treatment for metastatic disease.

This study is a basket trial with two strata(NSCLC and other cancer). If MET exon 14 skipping mutation or MET amplification(copy number gain ≥6.0 ) is detected by NGS method, then confirmation of genetic findings by Molecular Steering Committee will be followed. Patient can participate in this trial after confirmation of genetic analysis and reviewing other inclusion/exclusion criteria.

Experimental: Arm 1_NSCLC Patients with non-small cell lung cancer (NSCLC) harboring MET alteration Experimental: Arm 2_Other solid tumors Solid tumors excluding NSCLC harboring MET alteration

Tepotinib in Solid Tumors Harboring MET Alterations

A Phase II Study of Tepotinib in Patients With Solid Cancers Harboring c-MET Amplification or Exon 14 Mutation Who Progressed After Standard Treatment for Advanced/Metastatic Disease

Objective response will be determined according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by investigator.

Objective response is defined as either a confirmed complete response (CR) or partial response (PR) from first administration of trial treatment to first observation of progressive disease (PD). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD is defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

Progression free survival as assessed by investigators is defined as the time (in months) from the first administration of trial treatment to the date of the first documentation of PD (based on independent review) or death due to any cause within 84 days of the last tumor assessment, whichever occurs first

Objective disease control is defined as either a confirmed CR or PR, or stable disease (SD) lasting at least 12 weeks (84 days) as assessed by investigator. CR: Disappearance of all evidence of target and non-target lesions.

Overall survival is defined as the time (in months) from first trial treatment administration to the date of death.

This outcome measure will be presented as the percentage of subjects with any adverse event (AE). Percentages are calculated using total number of subjects per treatment cohort as the denominator.

Merck KGaA, Darmstadt, Germany

Chungbuk National University Hospital

Participants with NSCLC with MET exon 14 skipping mutations, irrespective of MET gene copy number (GCN) will take 400 mg tablet orally twice per day

Participants with NSCLC with high level MET amplification will take 400 mg tablet orally twice per day

150 mg and 200 mg tablets for oral administration

capmatinib

The purpose of this study is to determine if neoadjuvant capmatinib can improve outcomes in participants with stages I-IIIA non-small cell lung cancer with MET exon 14 mutations and/or high MET amplification beyond those achieved with surgery, chemotherapy, and radiation.

This trial is a phase II, two cohort study of neoadjuvant capmatinib treatment (pre-surgery) which will be given for 8 weeks prior to a surgical resection and then followed by a three year adjuvant capmatinib treatment (post surgery). Following treatment, there will be a two year survival follow-up. The two molecularly defined cohorts will be enrolled in parallel. Approximately 38 evaluable participants will be enrolled in the study.

During treatment participants will visit their treating physician to assess overall health status which will include lab-work and other safety assessments. Survival follow-up will be every 6 months which can be conducted via a telephone visit for up to approximately 2 years after end of treatment.

Phase II of Neoadjuvant and Adjuvant Capmatinib in NSCLC

Phase II Trial of Neoadjuvant and Adjuvant Capmatinib in Participants With Stages IB-IIIA, N2 and Selected IIIB (T3N2 or T4N2) NSCLC With MET Exon 14 Skipping Mutation or High MET Amplification (Geometry-N)

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on https://www.clinicalstudydatarequest.com/.

MPR rate in each cohort defined as the percentage of participants with ≤ 10% residual viable cancer cells

Complete pathologic response (pCR) rate is defined as the percentage of participants with no residual viable cancer cells.

Overall response rate (ORR) is defined as the percentage participants with best overall response (BOR) of complete response (CR) or partial response ( PR) according to RECIST v1.1

The occurrence of adverse events will be reported from first day of treatment through end of treatment plus 30 days.

Serious adverse events which are treatment related will be reported through the end of study participation. Adverse events also may be detected or through physical examination findings, laboratory test findings, or other assessments.

Defined as the time from end of surgery (start of adjuvant therapy) until the recurrence of cancer or death due to any cause.

Novartis Pharmaceuticals

Trametinib

Protein Kinase Inhibitors

Patients receive 200 - 400 mg capmatinib orally, twice a day and 1.0 or 1.5 mg trametinib orally once a day on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

Patients will receive the recommended phase 2 dose (RP2D) or capmatinib in combination with trametinib determined by the safety profile of the Phase 1 group. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

Capmatinib

Lisa Tan

Collin M. Blakely, MD, PhD

Johnathan Riess, MD, MS

Collin M Blakely, MD, PhD

This phase I/Ib trial studies the side effects and best doses of capmatinib plus trametinib when given together for the treatment of patients with MET exon 14 skipping mutation non-small cell lung cancer that has spread to other places in the body (metastatic). Capmatinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Trametinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps stop the spread of cancer cells. Capmatinib and trametinib are "targeted therapies." These targeted therapies work by detecting and targeting a mutation in the MET gene. Giving Capmatinib and trametinib may kill more tumor cells in patients with metastatic non-small cell lung cancer.

PRIMARY OBJECTIVES:

I. To identify recommended phase II dose (RP2D) of capmatinib in combination with trametinib in non-small cell lung cancer (NSCLC) with MET 14 exon mutation, MET amplification, or MET fusion (Phase I).

II. To further characterize the safety profile of the RP2D of capmatinib in combination with trametinib in MET-exon14 mutated NSCLC (Phase Ib).

SECONDARY OBJECTIVES:

I. To further characterize the safety profile of the combination of capmatinib and trametinib in NSCLC with MET exon 14 mutation, MET amplification, or MET fusion (Phase I).

II. To determine preliminary efficacy ofcapmatinib in combination with trametinib in MET-exon14 mutated NSCLC (Phase Ib)

EXPLORATORY OBJECTIVES:

I. To evaluate the pharmacokinetics of capmatinib in combination with trametinib.

II. To identify biomarkers of response to capmatinib and trametinib. III. To identify mechanisms of resistance tocapmatinib and trametinib.

OUTLINE: This is a phase I dose-escalation study of capmatinib and trametinib followed by a phase Ib dose expansion study.

Patients receive capmatinib orally (PO) twice daily (BID) and trametinib PO once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 12 months.

Capmatinib Plus Trametinib for the Treatment of Metastatic Non-small Cell Lung Cancer With MET Exon 14 Skipping Mutation

A Multicenter Phase I/Ib Study of Capmatinib Plus Trametinib in Patients With Metastatic MET Exon 14 Skipping Mutation Positive NSCLC

Proportion of participants who experience a DLT for capmatinib in combination with trametinib in Phase I. A dose limiting toxicity (DLT) will be defined as any adverse event that are considered by the investigator to be at least possibly related to capmatinib or trametinib and are observed during the first 28 days of treatment (Cycle 1).

Proportion of participants with treatment-emergent Adverse Events, will be reported as preferred terms using Medical Dictionary for Regulatory Activities (MedDRA).as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0) in Phase Ib (Dose Expansion).

Proportion of participants with Adverse Events, as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0 in Phase Ib

The ORR is defined as the best overall response recorded from the start of the treatment until disease progression or recurrence assessed over a 1-year period from the start of treatment using RECIST version 1.1 criteria. The percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be determined.

DCR will be defined as the percentage of patients who have achieved CR, PR, or SD (based on RECIST 1.1 criteria) for at least 12 weeks. The mean DCR and the standard deviation of DCR will be summarized.

PFS will be calculated as 1+ the number of days from the first dose of study drugs to documented radiographic progression or death due to any cause. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. The Kaplan-Meier analysis will be used to calculate the median PFS with 95% confidence interval.

OS will be calculated as 1+ the number of days from the first dose of study drugs to death due to any cause. The Kaplan-Meier analysis will be used to calculate the median PFS with 95% confidence interval.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Neoadjuvant Immunotherapy in Rare Mutations Localized NSCLC	NCT05800340	Non-Small Cell ... RET Driver Muta... BRAF V600 Mutat... Erb-B2 Receptor... MET Amplificati... MET Exon 14 Ski...	Toripalimab Nab paclitaxel Pemetrexed Carboplatin	18 Years -	Guangdong Provincial People's Hospital
Neoadjuvant Immunotherapy in Rare Mutations Localized NSCLC	NCT05800340	Non-Small Cell ... RET Driver Muta... BRAF V600 Mutat... Erb-B2 Receptor... MET Amplificati... MET Exon 14 Ski...	Toripalimab Nab paclitaxel Pemetrexed Carboplatin	18 Years -	Guangdong Provincial People's Hospital
Neoadjuvant Immunotherapy in Rare Mutations Localized NSCLC	NCT05800340	Non-Small Cell ... RET Driver Muta... BRAF V600 Mutat... Erb-B2 Receptor... MET Amplificati... MET Exon 14 Ski...	Toripalimab Nab paclitaxel Pemetrexed Carboplatin	18 Years -	Guangdong Provincial People's Hospital
Tepotinib in Solid Tumors Harboring MET Alterations	NCT04647838	Solid Tumor MET Exon 14 Ski... MET Amplificati...	Tepotinib	19 Years -	Chungbuk National University Hospital
Phase II of Neoadjuvant and Adjuvant Capmatinib in NSCLC	NCT04926831	Non-small Cell ...	capmatinib	18 Years - 90 Years	Novartis
Capmatinib Plus Trametinib for the Treatment of Metastatic Non-small Cell Lung Cancer With MET Exon 14 Skipping Mutation	NCT05435846	Metastatic Lung... Stage IV Lung C...	Capmatinib Trametinib	18 Years -	University of California, San Francisco

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