Neoplasms

All Conditions

Neoplasms, Second Primary

All Drugs and Chemicals

Amino Acids

Immunomodulating Agents

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme 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

Blood and Lymph Conditions

Skin and Connective Tissue Diseases

Digestive System Diseases

Gland and Hormone Related Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Symptoms and General Pathology

Respiratory Tract (Lung and Bronchial) Diseases

Immune System Diseases

Nervous System Diseases

Heart and Blood Diseases

Musculoskeletal Diseases

Diseases and Abnormalities at or Before Birth

Nutritional and Metabolic Diseases

Rare Diseases

Leukemia

Breast Neoplasms

Adenocarcinoma

Pancreatic Neoplasms

Glioma

Osteosarcoma

Sarcoma

Carcinoma, Renal Cell

Neoplasm Metastasis

Lung Neoplasms

Lymphoma

Hematologic Neoplasms

Ataxia

Cerebellar Ataxia

Leukemia, T-Cell

Precursor T-Cell Lymphoblastic Leukemia-Lymphoma

Telangiectasis

Bone Neoplasms

Kidney Neoplasms

Ataxia Telangiectasia

Colorectal Neoplasms

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Neoplasms, Glandular and Epithelial

Neoplastic Processes

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Breast Diseases

Skin Diseases

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Hematologic Diseases

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Bone Diseases

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Intestinal Neoplasms

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Pancreatic Cancer

Renal Cell Carcinoma

Soft Tissue Sarcoma

Lymphosarcoma

Acute Graft Versus Host Disease

Leukemia, T-cell, Chronic

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Neuroepithelioma

Antineoplastic Agents

Anti-Infective Agents

Gemcitabine

Paclitaxel

Albumin-Bound Paclitaxel

Carboplatin

Irinotecan

Doxorubicin

Liposomal doxorubicin

Lomustine

Tubulin Modulators

Antimitotic Agents

Antimetabolites

Anti-Bacterial Agents

Antibiotics, Antitubercular

Topoisomerase I Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Drugs: Gemcitabine - 21 day cycle. 9-ING-41

Drugs: Nab-paclitaxel. Gemcitabine - 28 day cycle. 9-ING-41.

Drugs: Paclitaxel. Carboplatin. 9-ING-41.

Starting dose of-9-ING-41 will be administered on Day 1 and 4 each week of a 21-day cycle. 9-ING-41 will be administered intravenously over 60 minutes.

9-ING-41

Gemcitabine 1250 mg/m2 as a 30-minute intravenous infusion on Days 1 and 8 of a 21-day cycle

Gemcitabine - 21 day cycle

Doxorubicin 75 mg/m2, intravenous bolus on Day 1 of a 21-day cycle up to a maximum lifetime dose of 550 mg/m2.

Doxorubicin.

Lomustine 30 mg/m² orally as a single dose, weekly for twelve weeks.

Carboplatin AUC 6 IV over 1 hour on Day 1 of a 21-day cycle.

Carboplatin.

Nab-paclitaxel 125 mg/m2 intravenously on Days 1, 8 and 15 of a 28-day cycle

Nab paclitaxel.

Paclitaxel 175 mg/m2 intravenously over 3 hours on Day 1 of a 21-day cycle.

Paclitaxel.

Gemcitabine 1000 mg/m2 intravenously over 30-minutes on Days 1, 8 and 15 of a 28-day cycle

Gemcitabine - 28 day cycle

Irinotecan 350 mg/m2 intravenously over 90-minutes on Day 1 of a 21-day cycle

GSK-3β is a potentially important therapeutic target in human malignancies. The Actuate 1801 Phase 1/2 study is designed to evaluate the safety and efficacy of 9-ING-41, a potent GSK-3β inhibitor, as a single agent and in combination with cytotoxic agents, in patients with refractory cancers.

9-ING-41 is a first-in-class, intravenously administered, maleimide-based small molecule potent selective GSK-3β inhibitor with significant pre-clinical antitumor activity. GSK-3 is a serine/threonine kinase initially described as a key regulator of metabolism and has a role in diverse disease processes including cancer, immune disorders, pathologic fibrosis, metabolic disorders, and neurological disorders. GSK-3 has two ubiquitously expressed and highly conserved isoforms, GSK-3α and GSK-3β, with both shared and distinct substrates and functional effects. GSK-3β is particularly important in tumor progression and modulation of oncogenes (including beta-catenin, cyclin D1 and c-Myc), cell cycle regulators (e.g. p27Kip1) and mediators of epithelial-mesenchymal transition (e.g. zinc finger protein SNAI1, Snail). Aberrant overexpression of GSK-3β has been shown to promote tumor growth and chemotherapy resistance in various solid tumors including colon, ovarian, and pancreatic cancers and glioblastoma through differential effects on the pro-survival nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and c-Myc pathways as well on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and p53-mediated apoptotic mechanisms. GSK-3β helps maintain malignant cell survival and proliferation, particularly in terms of mediating resistance to standard anti-cancer therapies, through the NF-κB pathway. GSK-3β has been established as a potential anticancer target in human bladder, breast, colorectal, glioblastoma, lung, neuroblastoma, ovarian, pancreatic, prostate, renal and thyroid cancers as well as chronic lymphocytic leukemia and lymphomas.

9-ING-41 is a small molecule potent selective GSK-3β inhibitor with broad spectrum pre-clinical antitumor activity. It's modes of action include downregulation of NF-κB and decreasing the expression NF-κB target genes including cyclin D1, Bcl-2, anti-apoptotic protein (XIAP) and B-cell lymphoma-extra large (Bcl-XL) leading to inhibition of tumor growth in multiple solid tumor cell and lymphoma lines and patient derived xenograft (PDX) models. NF-κB is constitutively active in cancer cells and promotes anti-apoptotic molecule expression. NF-κB activation is particularly important in cancer cells that have become chemo- and/or radio-resistant. 9-ING-41 also has significant activity in pre-clinical models of pathological pleural and pulmonary fibrosis. 9-ING-41 has significant in vitro and in vivo activity as a single agent and/or in combination with standard cytotoxic chemotherapies in a spectrum of solid tumors and hematological malignancies including bladder, breast, glioblastoma, neuroblastoma, pancreatic, sarcomas, and renal cancers as well as lymphomas.

The 1801 had three parts:

* Completed: Part 1 (9-ING-41 as monotherapy): The standard 3+3 dose escalation design will be applied to all dose cohorts until the Maximum Tolerated Dose (MTD) or Recommended Phase 2 Dose (RP2D) is identified.
* Completed: 9-ING-41 combined with standard anticancer agents: The 3+3 dose escalation study design will be used for 8 chemotherapy combination regimens (9-ING-41 plus gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, nab-paclitaxel plus gemcitabine, paclitaxel plus carboplatin, pemetrexed plus carboplatin) to identify the MTD/RP2D of each regimen.
* Part 3: A randomized Phase 2 study of 9-ING-41 either once or twice weekly with gemcitabine and nab-paclitaxel (GA) versus GA alone for patients with previously untreated metastatic or locally advanced pancreatic cancer is now open.

9-ING-41 in Patients With Advanced Cancers

Phase 1/2 Study of 9-ING-41, a Glycogen Synthase Kinase-3 Beta (GSK-3β) Inhibitor, as a Single Agent and Combined With Chemotherapy, in Patients With Refractory Hematologic Malignancies or Solid Tumors

The standard assessments used to assign a score to any affected organ system as per the NCI CTCAE 4.03 will be conduced at each protocol-specified timepoint.

To determine the 1-year survival rate of patients treated on the 9-ING-41 schedule chosen from the run-in stage of the study compared to the control arm

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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
9-ING-41 in Patients With Advanced Cancers	NCT03678883	Cancer Pancreatic Canc... Sarcoma Renal Cancer Refractory Canc... Refractory Neop... Refractory Non-... Pancreatic Aden... Resistant Cance... Neoplasm Metast... Neoplasm of Bon... Neoplasm, Breas... Neoplasm of Lun... Neoplasms,Color... Neoplasms Pancr... Malignant Gliom... Malignancies Malignancies Mu... Bone Metastases Bone Neoplasm Bone Cancer Pancreas Cancer Pancreatic Neop... Breast Neoplasm... Acute T Cell Le...	9-ING-41 Gemcitabine - 2... Doxorubicin. Lomustine Carboplatin. Nab paclitaxel. Paclitaxel. Gemcitabine - 2... Irinotecan	18 Years -	Actuate Therapeutics Inc.
Coronavirus Disease 2019 (COVID-19) Vaccination in Cancer Patients	NCT04953065	Malignancies Mu...	COVID-19 vaccin...	18 Years - 89 Years	Milton S. Hershey Medical Center
A Study to Evaluate the Effect of 2 Drugs on the Pharmacokinetics of BMS-986205 in Healthy Subjects	NCT03346837	Malignancies Mu...	BMS-986205 Itraconazole Rifampin	18 Years - 50 Years	Bristol-Myers Squibb
Anti-PD-1 Antibody Alone or in Combination With Decitabine/Chemotherapy in Relapsed or Refractory Malignancies	NCT02961101	Malignancies Mu...	Anti-PD-1 antib... Decitabine Chemotherapy	12 Years - 75 Years	Chinese PLA General Hospital
Anti-PD-1 Antibody Alone or in Combination With Decitabine/Chemotherapy in Relapsed or Refractory Malignancies	NCT02961101	Malignancies Mu...	Anti-PD-1 antib... Decitabine Chemotherapy	12 Years - 75 Years	Chinese PLA General Hospital
Anti-PD-1 Antibody Alone or in Combination With Decitabine/Chemotherapy in Relapsed or Refractory Malignancies	NCT02961101	Malignancies Mu...	Anti-PD-1 antib... Decitabine Chemotherapy	12 Years - 75 Years	Chinese PLA General Hospital
Coronavirus Disease 2019 (COVID-19) Vaccination in Cancer Patients	NCT04953065	Malignancies Mu...	COVID-19 vaccin...	18 Years - 89 Years	Milton S. Hershey Medical Center

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