Neoplasms

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Neuroectodermal Tumors, Primitive

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Nevus

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Antineoplastic Agents

All Drugs and Chemicals

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Bevacizumab

Hydroxychloroquine

Trametinib

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Leflunomide

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Antimalarials

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Antiparasitic Agents

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Combination of MEK Inhibitor and Hydroxychloroquine ( Plaquenil)

100 mg daily for 3 days at the loading dose, then 20 mg daily at the standard dose.

Use of one of the possible MEK-inhibitor options:

Trametinib 2 mg once daily orally; Cobimetinib 60 mg on days 1-21, break 7 days, cycle 28 days orally; Binimetinib 45 mg 2 times a day daily orally. + Hydroxychloroquine 600 mg 2 times a day daily orally.

± Bevacizumab 7.5 mg/m² every 3 weeks intravenously.

The combination of MEK inhibitor + hydroxychloroquine( plaquenil) ± bevacizumab

Evgeny Imyanitov

Liliya Baboshkina

There is a huge variety of nucleotide substitutions that activate RAS. The search for new "universal" drugs for the RAS pathway that either interfere with RAS upregulation upstream in the signaling pathway or offset the consequences of RAS activation is important for improving therapeutic outcomes for patients with refractory malignancies.

The use of leflunomide or the combination of MEK inhibitor + hydroxychloroquine ± bevacizumab is promising for patients with mutations in RAS cascade genes who have failed all existing treatment standards.

Mutations in the RAS gene are a common cause for the development of many tumors.

It is of practical interest to study the potential efficacy of several drugs registered for the treatment of other diseases, which may also be able to affect various parts of the RAS pathway.

Leflunomide, with its active metabolite , inhibits the enzyme dihydroorotate dehydrogenase (DHODH). DHODH plays an essential role in the biosynthesis of pyrimidine, which is particularly important for the growth of RAS mutant cells.

Tumors with KRAS, NRAS, and HRAS mutations are characterized by increased MEK kinase activity. The combination of MEK inhibitor + hydroxychloroquine ± bevacizumab is able to affect MEK kinase activity by direct inhibition as well as regulation of autophagy, which is controlled in this case by the antimalarial drug hydroxychloroquine.

The use of bevacizumab is appropriate because there is evidence of its efficacy in the treatment of patients with colorectal cancer, including colorectal cancer with mutations in the KRAS gene.

Leflunomide or Combination of MEK Inhibitor and Hydroxychloroquine for Refractory Patients With RAS Mutations

New Therapeutic Approaches for Tumors With RAS Gene Mutations

Objective response rate was assigned for a subject if the subject displayed either complete response (CR) or partial response (PR) per RECIST version 1.1

European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life (QoL) in cancer participants. It consisted of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, role, cognitive, emotional, social), and 9 symptom scales/items (Fatigue, nausea and vomiting, pain, dyspnoea, sleep disturbance, appetite loss, constipation, diarrhea, financial impact. The EORTC QLQ-C30 GHS/QoL score ranges from 0 to 100; High score indicates better GHS/QoL. Score 0 represents: very poor physical condition and QoL. Score 100 represents: excellent overall physical condition and QoL.

Progression-free survival was defined as the time from start treatment to subsequent confirmed progression per RECIST version 1.1, or death (whichever occurred first), measured in weeks and months. For PFS assessment clinical progression (i.e., treatment discontinuation due to progression of disease) was also considered as an event.

Overall survival was defined as the time from start treatment to subsequent death, measured in weeks and months.

N.N. Petrov National Medical Research Center of Oncology

Oncologist

Neoplasms, Second Primary

Amino Acids

Immunomodulating Agents

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

Living cancer patients with histologically confirmed rare molecular alterations in their tumours, such as in ALK, EGFR, ROS1, BRAF, and KRAS G12C from participating sites/cancer centres across Canada.

Deceased cancer patients who had histologically confirmed rare molecular alterations in their tumours, such as in ALK, EGFR, ROS1, BRAF, and KRAS G12C from participating sites/cancer centres across Canada.

All cancer patients without rare molecular alterations in their tumours. This group will be established in order to determine baseline characteristics and outcomes, including treatment outcomes, of more standard treatments such as systemic chemotherapy or immunotherapy.

Observing cancer patients who have received or are currently receiving tyrosine kinase inhibitors (TKIs) or other molecularly targeted therapies for their cancer treatment.

Cancer treatment with tyrosine kinase inhibitors (TKIs) or other molecularly targeted therapeutic agents.

Prospectively enrolled participants will be provided with survey packets comprised of different PRO instruments at the initial/baseline visit, at 3 month follow up intervals and at the time when treatment/therapy is changed.

Patient-reported outcomes (PROs)

Roula Raptis, MSc

Geoffrey Liu, MD, MSc

Vishal Navani, MA (Oxon), MBBS, MRCP, FRACP

Quincy Siu-Chung Chu, MD, FRCPC

Cheryl Ho, MD, FRCPC

Shantanu Banerji, MD, FRCPC

Luisa Galvis-Gomez, MD

Elizabeth Faour, MD

Stephanie Snow, MD, FRCPC

Parneet Cheema, MD, FRCPC

Rosalyn Juergens, MD, PhD

Sofia Genta, MD

Sara Kuruvilla, MD, FRCPC

Paul Wheatley-Price, MBChB, FRCP(UK), MD

Abhenil Mittal, MD

Olexiy Aseyev, MD

Devalben Patel, BSc, MLT

Ronald Burkes, MD, FRCPC

Ines Menjak, MD, FRCPC

Normand Blais, MD, MSc

Kevin Jao, MD, PhD

Jason Agulnik, MD

Jonathan Spicer, MD, PhD

Nicholas Meti, MD

Nicolas Marcoux, MD, FRCPC

Philippe Joubert, MD, PhD

Nicole Bouchard, MD

Ayesha Bashir, MD, FRCPC

Sunil Yadav, MD

This study will collect data on Canadian cancer patients that have uncommon/rare changes in their tumours, such as alterations/rearrangements in the genetic material inside cells - known as deoxyribonucleic acid, or DNA, which acts as a map and gives directions to the cells on how to make other substances the body needs - because some of these changes have been found to respond to different drugs that help to stop the cancer. These rare changes occur in genes such as but not limited to ALK, EGFR, ROS1, BRAF, and NTRK which have targeted drugs in a family known as tyrosine kinase inhibitors (TKIs), and KRAS G12C mutation, which now has a targeted inhibitor drug therapy for patients with non small cell lung cancer (NSCLC). The goals for the study are to compare the natural history of such cancers and the treatment outcomes, including toxicities and patient-reported outcomes, for the different therapies.

Molecular heterogeneity in cancer tumours make it a complex disease to manage and treat. However, there have been significant advancements made in the detection of molecular alterations and we are able to now define distinct disease subtypes which permit targeted selection of therapies, thus optimizing treatment responses for patients and improving their survival.

With CARMA-BROS we will address the objectives that follow.

Primary Objectives:

1. To create a cohort of patients through which to better understand the natural history of disease in Canadian cancer patients with tumours that have been molecularly subtyped and identified to have rare molecular alterations.
2. To compare the natural history, stage distribution, treatment outcomes such as treatment effectiveness (composite of disease progression or death) and treatment toxicities across different patients with different molecular alterations, receiving different lines and types of therapy.

   Secondary Objectives:
3. To determine the incidence, time to development, prevalence, and outcomes of patients with specific patterns of spread, such as brain metastases compared to those without, by different therapies and by molecular alterations.
4. To better understand real-world treatment patterns of rare molecular alterations in the Canadian context, across geographic or other factors, and how treatment patterns evolve over time and as new therapies become available, how patients are investigated and how targeted and other biomarkers are used as part of clinical practice in these patients.
5. To assess quality of life in patients with rare molecular alterations across different stages, lines and types of therapy.
6. To perform exploratory health economic evaluations focused on the costs and benefits of managing patients with rare molecular alterations.
7. To perform biomarker analyses, where appropriate, to improve our understanding of these rare molecular alterations.

CAnadian CAncers With Rare Molecular Alterations (CARMA) - Basket Real-world Observational Study (BROS)

Composite of disease progression or death

Confirmed through imaging (MRI, CT) or determined through treatment indication(s), for example, brain radiation therapy (surrogate for presence of brain metastasis)

Prospectively enrolled participants will complete the following health related quality of life surveys: EORTC QLQ-C30 (core) and EORTC QLQ-LC13 (disease specific module)

Prospectively enrolled participants will complete the health related quality of life survey: EQ-5D-5L.

Prospectively enrolled participants will complete the "Work Productivity and Activity Impairment Questionnaire: General Health" (WPAI:GH) and other economic impact questions that capture indirect costs incurred as a result of their disease.

Takeda Canada, Inc.

Applied Health Research Centre

Programs for Assessment of Technology in Health Research Institute

AstraZeneca

Amgen

Bayer

AnHeart Therapeutics Inc.

University Health Network, Toronto

Glioma

Part A will evaluate the safety of NST-628 with advanced solid tumors and determine the recommended dose for expansion of NST-628.

Part B will evaluate the objective tumor response rate in subjects with advanced solid tumors harboring specified genetic alterations receiving NST-628 and evaluate the safety of NST-628 in subjects with advanced solid tumors in cohorts defined below:

i. Melanoma Cohorts

1. Activating NRAS mutations
2. Select BRAF alterations

ii. Non-Melanoma Cohorts:

1. Solid tumors with NRAS activating mutations
2. Solid tumors with KRAS activating mutations
3. Solid tumors with select BRAF alterations
4. Glioma with BRAF alterations

NST-628 is a small molecule non-covalent pan-RAF/MEK dual molecular glue targeting RAF and MEK nodes of MAPK pathway.

NST-628

Ann Marie Kennedy

Brianna Flores

Andrea Vandross, MD

Erica Torres

Naga Cheedella, MD

Blake Patterson

Mohamad Salkeni, MD

Shiena Lemin

Charlotte Lemech, MD

Jia (Jenny) Liu, MD

Sarah McLennan

Victoria Atkinson, MD

Scott McGregor

Omar Faruque, MD

Meggan O'Riley

Ganessan Kichenadasse, MD

This is a two-part Phase 1, open label, multi-center, single arm, non-randomized, multiple dose, safety, pharmacokinetic (PK) and preliminary efficacy study of single agent NST-628 in adult patients with MAPK pathway mutated/dependent advanced solid tumors who have exhausted standard treatment options.

The study includes two parts, a dose escalation part (Part A) followed by a dose expansion part (Part B). Part A will estimate the maximum tolerated dose (MTD) in dose escalation cohorts in patients with advanced solid tumors for whom no standard therapy is available in order to establish the recommended dose for expansion (RDE). Successive cohorts of subjects will receive escalating doses of NST-628 orally once daily in 28-day cycles.

Bayesian Optimal Interval (BOIN) method will be used for dose escalation.

Once MTD is reached or dose escalation is stopped prior to reaching MTD and provisional RDE selected, the provisional RDE level will be expanded. If warranted by dose/toxicity/anti-tumor activity observations, additional, lower dose level(s) may also be expanded.

Part B of the study will include up to 6 cohorts of approximately up to 30 subjects each with select MAPK pathway mutant solid tumors enrolled at the RDE in order to explore benefit from treatment as suggested by preclinical findings and will better define the safety profile of NST-628 at the RDE. Additional safety information gathered in Part B may be used to modify the dose recommended for future studies.

The end of the study is the last visit of the last subject.

A Study to Investigate the Safety and Efficacy of NST-628 Oral Tablets in Subjects With Solid Tumors

A Phase I, Open Label Single-arm Two-part Study to Investigate Safety, Pharmacokinetics, and Preliminary Efficacy of Pan-RAF/MEK Glue NST-628 Oral Tablets in Subject With Solid Tumors Harboring Genetic Alterations in the MAPK Pathway and With Other Solid Tumors

Objective response per RECIST v. 1.1 or other response assessment tool standard for a given tumor type.

PFS defined as the time to first occurrence of disease progression per RECIST v1.1 (or other response assessment tool standard for a given tumor type) or death

Overall survival (OS) defined as the time to death

Nested Therapeutics, Inc

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Leflunomide or Combination of MEK Inhibitor and Hydroxychloroquine for Refractory Patients With RAS Mutations	NCT06229340	RAS Mutation Ras (Kras or Nr... Colorectal Canc... Pancreas Cancer Lung Cancer Melanoma Refractory Canc...	Leflunomide The combination...	18 Years - 85 Years	N.N. Petrov National Medical Research Center of Oncology
CAnadian CAncers With Rare Molecular Alterations (CARMA) - Basket Real-world Observational Study (BROS)	NCT04151342	Cancer Malignancies Mu... Malignant Solid... Cancer, Therapy... Molecular Seque... Genetic Alterat... Gene Fusion Receptor Tyrosi... RTK Family Gene... Ras (Kras or Nr...	Cancer treatmen... Patient-reporte...	18 Years -	University Health Network, Toronto
Leflunomide or Combination of MEK Inhibitor and Hydroxychloroquine for Refractory Patients With RAS Mutations	NCT06229340	RAS Mutation Ras (Kras or Nr... Colorectal Canc... Pancreas Cancer Lung Cancer Melanoma Refractory Canc...	Leflunomide The combination...	18 Years - 85 Years	N.N. Petrov National Medical Research Center of Oncology
A Study to Investigate the Safety and Efficacy of NST-628 Oral Tablets in Subjects With Solid Tumors	NCT06326411	Oncology MEK Mutation RAF Gene Mutati... Ras (KRAS or NR... Melanoma NSCLC Glioma Solid Tumor, Ad... MAPK Pathway Ge...	NST-628	18 Years -	Nested Therapeutics, Inc
Leflunomide or Combination of MEK Inhibitor and Hydroxychloroquine for Refractory Patients With RAS Mutations	NCT06229340	RAS Mutation Ras (Kras or Nr... Colorectal Canc... Pancreas Cancer Lung Cancer Melanoma Refractory Canc...	Leflunomide The combination...	18 Years - 85 Years	N.N. Petrov National Medical Research Center of Oncology

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