Neoplasms

Digestive System Diseases

Gland and Hormone Related Diseases

All Conditions

Rare Diseases

Pancreatic Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Anti-Infective Agents

Antirheumatic Agents

All Drugs and Chemicals

Hydroxychloroquine

Growth Inhibitors

Antimalarials

Antiprotozoal Agents

Antiparasitic Agents

Enzyme Inhibitors

The research study procedures include screening for eligibility and study treatment. Study treatment will include evaluations, biopsies, and follow up visits. A treatment cycle will be defined as 28 consecutive days. Treatment will be administered on an outpatient basis.

Test the safety of study drugs in combination and define dose levels.

* LY3214996
* HCQ

The research study procedures include screening for eligibility and study treatment. Study treatment will include evaluations, biopsies, and follow up visits. A treatment cycle will be defined as 28 consecutive days. Treatment will be administered on an outpatient basis. Combined dosage per determined Lead-In Cohort

* LY3214996
* HCQ

The research study procedures include screening for eligibility and study treatment. Study treatment will include evaluations, biopsies, and follow up visits. A treatment cycle will be defined as 28 consecutive days.Treatment will be administered on an outpatient basis.

-LY3214996

Participants who are enrolled to Arm 2 who experience radiologic disease progression on monotherapy will have the option to cross-over to receive treatment with the combination. Crossover will occur at the treating investigator's discretion following consultation and approval from the overall principal investigator. Combined dosage per determined Lead-In Cohort

* LY3214996
* HCQ

HCQ will be administered by mouth twice daily continuously throughout each treatment per 28 day cycle

Hydroxychloroquine Sulfate

LY3214996-daily oral dosage per protocol per 28 day cycle

LY3214996

Kimberly Perez, MD

This study is evaluating the safety and efficacy of combining the study drug LY3214996 with hydroxychloroquine sulfate (HCQ) in patients with advanced pancreatic cancer.

* This is an open label, randomized, two arm, phase II with safety lead- in study exploring the anti-tumor activity of the extracellular signal-regulated kinase (ERK) inhibitor LY3214996 with and without hydroxychloroquine (HCQ) in patients with advanced pancreatic cancer.
* The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.

  * The safety lead-in will test the safety of a combination of investigational drugs and also try to define appropriate dosage. The names of the study drugs involved in this study are:

    * LY3214996
    * Hydroxychloroquine Sulfate (HCQ)
  * Following completion of a brief combination treatment safety lead-in cohort, participants will be randomized 1:1 for enrollment to one of two treatment arms:

    * Arm 1: receiving combination treatment with LY3214996 and HCQ
    * Arm 2: receiving monotherapy treatment with LY3214996

It is expected that about 52 people will take part in this research study

The U.S. Food and Drug Administration (FDA) has not approved LY3214996 as a treatment for any disease.

The U.S. Food and Drug Administration (FDA) has not approved HCQ for your specific disease but it has been approved for other uses.

LY3214996 +/- HCQ in Pancreatic Cancer

Phase II Trial of ERK Inhibition Alone and in Combination With Autophagy Inhibition in Patients With Metastatic Pancreatic Cancer

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Anti-tumor activity will be measured via disease control rate (DCR), which will be defined as the proportion of patients with complete response (CR), partial response (PR) or stable disease (SD) that persists for ≥ 4 months.

Kaplan and Meier to assess Overall survival (OS)

Eli Lilly and Company

Sponsor Investigator

Skin and Connective Tissue Diseases

Melanoma

Melanoma, Cutaneous Malignant

Skin Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

Trametinib

Dabrafenib

Dimethyl Sulfoxide

Protein Kinase Inhibitors

Protective Agents

Antioxidants

Patients receive dabrafenib mesylate PO BID, trametinib dimethyl sulfoxide PO QD, and hydroxychloroquine sulfate PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients receive dabrafenib mesylate PO BID, trametinib dimethyl sulfoxide PO QD, and placebo PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Dabrafenib Mesylate

Placebo Administration

Trametinib Dimethyl Sulfoxide

Ravi Amaravadi

This phase II trial investigates how well adding hydroxychloroquine to the standard treatment of dabrafenib and trametinib works to overcome resistance and delay disease progression in treating patients with stage IIIC or IV BRAF V600E/K melanoma. Hydroxychloroquine may cause cell death in tumor cells that rely on a process called "autophagy" for survival. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving hydroxychloroquine together with dabrafenib and trametinib may work better than dabrafenib and trametinib alone to shrink and stabilize the cancer.

PRIMARY OBJECTIVE:

I. To determine the rate of one year progression-free survival (PFS) when hydroxychloroquine sulfate (hydroxychloroquine) or placebo is added to dabrafenib mesylate (dabrafenib) and trametinib dimethyl sulfoxide (trametinib) in advanced BRAFV600E/K melanoma.

SECONDARY OBJECTIVES:

I. To compare the PFS of both arms. II. To evaluate the best overall response rate by treatment arm. III. To evaluate the complete response (CR) rate by treatment arm. IV. To evaluate the adverse event rate by treatment arm. V. To evaluate overall survival (OS) by treatment arm.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive dabrafenib mesylate orally (PO) twice daily (BID), trametinib dimethyl sulfoxide PO once daily (QD), and hydroxychloroquine sulfate PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive dabrafenib mesylate PO BID, trametinib dimethyl sulfoxide PO QD, and placebo PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

Testing Dabrafenib and Trametinib With or Without Hydroxychloroquine in Stage IIIC or IV BRAF V600E/K Melanoma

The BAMM2 (BRAF, Autophagy, MEK Inhibition in Melanoma) Study: A Randomized Double Blind Phase II Study of Dabrafenib and Trametinib With or Without Hydroxychloroquine in Advanced BRAF V600E/K Melanoma

Estimated from the Kaplan-Meier curves and compared by treatment arm. A test statistic of the difference in one-year PFS rates divided by the square root or the sum of the variances will be used with a normal approximation. Progression will be evaluated based on international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).

Will be estimated using the method of Kaplan-Meier by treatment arm and compared using the log-rank test. In this analysis, all cases with PFS assessed (including cases with censored \< one-year) will be included. Progression will be evaluated based on international criteria proposed by the revised RECIST guideline (version 1.1).

Will be estimated by treatment arm and 95% confidence intervals (CIs) will be provided. Response will be defined by the RECIST guidelines (version 1.1).

Will be estimated by treatment arm and 95% CIs will be provided. Response will be defined by the RECIST guidelines (version 1.1).

Overall survival will be described using the method of Kaplan-Meier by treatment arm.

Will be monitored carefully throughout the study and will be summarized by treatment arm. Adverse events will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).

National Cancer Institute (NCI)

ECOG-ACRIN Cancer Research Group

Immune System Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Symptoms and General Pathology

Autoimmune Diseases

Kidney Diseases

Necrosis

Nephritis

Proteinuria

Glomerulonephritis, IGA

Urologic Diseases

Glomerulonephritis

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Male Urogenital Diseases

Urination Disorders

Urological Manifestations

IgA Nephropathy

Antihypertensive Agents

Vasoconstrictor Agents

Valsartan

Interferons

Interferon-alpha

Immunoglobulin A

Angiotensin II

Giapreza

Angiotensinogen

Angiotensin II Type 1 Receptor Blockers

Angiotensin Receptor Antagonists

valsartan (160mg/d) and Hydroxychloroquine Sulfate ( 400mg/d, twice daily)

RUITONG GAO, MD

Ruitong Gao, MD

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis in the world.There is to date no curative therapy for patients with IgAN.It is considered that dendritic cells, Toll-like receptor (TLR) 9 and cytokines interleukin-6 (IL-6), and interferon-alpha (IFN-a) and tumor necrosis factor-alpha (TNF-α), play an important role in the aberrant mucosal response. Hydroxychloroquine is an antimalarial agent and had a notable impact on immune activation by the reduction of circulating activated immune cells that including decreased TLR-expressing cells, reduced IFN-secreting plasmacytoid dendritic cells, reduced production of inflammatory cytokines including interferon alpha, IL-6 and TNF alpha. Recent studies showed hydroxychloroquine had a benefit for renal remission and could retard the onset of renal damage in patients with lupus nephritis. hydroxychloroquine may have the potential effect in IgA nephropathy, alleviated the proteinuria and had the renal protect effect. This will be a single center, prospective, randomized, controlled study to assess the utility of hydroxychloroquine in IgAN patients.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis in the world. Its estimated frequency is at least 2.5 cases per year per 100,000 adults. The glomerulopathy usually progressed slowly leading to end stage renal disease (ESRD). ESRD developed in 20%-40% of patients after 20 years. Given its complex and as yet incompletely understood pathogenetic mechanisms, there is to date no curative therapy for patients with IgAN.

Although pathogenesis of IgAN is still obscure, underglycosylated IgA-containing immune-complex including IgG or IgA antibodies against the hinge region of IgA1 are key factors for IgA nephropathy. Aberrant mucosal immune response might lead to increased production of underglycosylated IgA1. It is considered that dendritic cells, Toll-like receptor (TLR)9, and cytokines interleukin-6 (IL-6), , interferon-alpha (IFN-a) and tumor necrosis factor-alpha (TNF-α), play an important role in the aberrant mucosal response.

Hydroxychloroquine is an antimalarial agent and had a notable impact on immune activation by the reduction of circulating activated immune cells that including decreased TLR-expressing cells, reduced IFN-secreting plasmacytoid dendritic cells, reduced production of inflammatory cytokines including interferon alpha, IL-6 and TNF alpha. Recent studies showed hydroxychloroquine had a benefit for renal remission and could retard the onset of renal damage in patients with lupus nephritis.

Therefore, hydroxychloroquine, targeting dendritic cells, TLR, IL-6, IFN-α and TNF-α，may have the potential effect in IgA nephropathy, alleviated the proteinuria and had the renal protect effect. This will be a single center, prospective, randomized, controlled study to assess the utility of hydroxychloroquine added to valsartan in IgAN patients.

Hydroxychloroquine Sulfate Alleviates Persistent Proteinuria in IgA Nephropathy

Hydroxychloroquine Sulfate Alleviates Persistent Proteinuria in IgA Nephropathy:a Single Center Prospective Randomized Controlled Study

CR: proteinuria \<0.3 g/24 hr with no worsening of renal function (\<15% estimated glomerular filtration rate(eGFR) reduction from Baseline).PR: proteinuria \<3.5g/24 hrs but ≥0.3g/24 hrs and a decrease of \>50% from Baseline based on 24 hours pooled urine, with no worsening of renal function(\<15% eGFR reduction from Baseline). eGFR at Baseline will be defined as the Day 0 values.

Proteinuria is being assessed at Weeks 0, 4, 12, 24 follow-up visits. Proteinuria is based on 24 hours pooled urine. Baseline is defined as the Day 0 values. The ratio is defined as the post-Baseline value divided by the Baseline value.

Serum creatinine is being assessed at Weeks 0, 4, 12, 24 follow-up visits. Baseline is defined as the Day 0 values. The ratio is defined as the post-Baseline value divided by the Baseline value.

eGFR is being assessed from levels of creatinine using the 4 variable version of the modification of diet in renal disease (MDRD) equation as recommended by national kidney foundation-chronic kidney disease (NKF-CKD) guidelines. eGFR is calculated at Weeks 0, 4, 12, 24 follow-up visits. Baseline is defined as the Day 0 values. The ratio is defined as the post-Baseline value divided by the Baseline value.

IgA levels in serum are being analyzed at Weeks 0, 4, 12, 24 follow-up visits. Baseline is defined as the Day 0 value. The ratio is defined as the post-Baseline value divided by the Baseline value.

Interleukin-6 levels in serum are being analyzed at Weeks 0, 4, 12, 24 follow-up visits by means of enzyme linked immunosorbent assay (ELISA). Baseline is defined as the Day 0 value. The ratio is defined as the post-Baseline value divided by the Baseline value.

Interferon alfa levels in serum are being analyzed at Weeks 0, 4, 12, 24 follow-up visits by means of enzyme linked immunosorbent assay (ELISA). Baseline is defined as the Day 0 value. The ratio is defined as the post-Baseline value divided by the Baseline value.

Tumor necrosis factor alpha levels in serum are being analyzed at Weeks 0, 4, 12, 24 follow-up visits by means of enzyme linked immunosorbent assay (ELISA). Baseline is defined as the Day 0 value. The ratio is defined as the post-Baseline value divided by the Baseline value.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
LY3214996 +/- HCQ in Pancreatic Cancer	NCT04386057	Pancreatic Canc... Advanced Cancer	Hydroxychloroqu... LY3214996	18 Years -	Dana-Farber Cancer Institute
Testing Dabrafenib and Trametinib With or Without Hydroxychloroquine in Stage IIIC or IV BRAF V600E/K Melanoma	NCT04527549	Clinical Stage ... Locally Advance... Pathologic Stag... Pathologic Stag... Unresectable Me...	Dabrafenib Mesy... Hydroxychloroqu... Placebo Adminis... Trametinib Dime...	18 Years -	Eastern Cooperative Oncology Group
Hydroxychloroquine Sulfate Alleviates Persistent Proteinuria in IgA Nephropathy	NCT02765594	Primary IgA Nep...	Hydroxychloroqu... Valsartan	18 Years - 60 Years	Peking Union Medical College Hospital
LY3214996 +/- HCQ in Pancreatic Cancer	NCT04386057	Pancreatic Canc... Advanced Cancer	Hydroxychloroqu... LY3214996	18 Years -	Dana-Farber Cancer Institute
Testing Dabrafenib and Trametinib With or Without Hydroxychloroquine in Stage IIIC or IV BRAF V600E/K Melanoma	NCT04527549	Clinical Stage ... Locally Advance... Pathologic Stag... Pathologic Stag... Unresectable Me...	Dabrafenib Mesy... Hydroxychloroqu... Placebo Adminis... Trametinib Dime...	18 Years -	Eastern Cooperative Oncology Group

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