Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Antineoplastic Agents

All Drugs and Chemicals

Pomalidomide

Immunologic Factors

Angiogenesis Inhibitors

Growth Inhibitors

Comparison of different dosages and schedules of drug

Madhav Dhodapkar, M.D.

Lenalidomide has clinical activity in myeloma. The closely related compound, Pomalidomide, may have clinical activity in patients who have previously been treated with lenalidomide and who no longer respond to it. The mechanism of anti-tumor effects of these drugs has been attributed to several effects including anti-angiogenesis, immune activation, and anti-proliferative effects. Recent studies have suggested that these agents can mediate surprisingly rapid biologic effects on human monocytes and T cells. Our hypothesis is that the proximate effects of these drugs will be sensitive and quantitative surrogates of subsequent effects including activation of tumor antigen specific T cells as well as innate immune cells. Understanding the correlation between the pharmacodynamics of these effects with downstream activation using quantitative assays will facilitate the rational development of pomalidomide as immune-modulatory drug in diverse settings as well as its optimal development in myeloma therapy.

Multiple Myeloma (MM) is a common hematologic malignancy characterized by clonal expansion of transformed plasma cells (PCs) in the bone marrow1. Over the past decade, the introduction of immunomodulatory agents (such as thalidomide and lenalidomide) and proteasome inhibitors (such as bortezomib) as effective therapies has altered the therapeutic landscape for multiple myeloma (MM). Following the approval and establishment of thalidomide-containing regimens, such as melphalan, prednisone and thalidomide (MPT) and Thal/Dex, as the standard first-line therapy for newly diagnosed MM (NDMM), lenalidomide in combination with dexamethasone (RD) was approved for the treatment of patients with previously treated multiple myeloma 1 (MM1). However, even with these newly approved agents, MM remains an incurable disease and most patients will eventually relapse and progress after multiple lines of different therapeutic regimens including both lenalidomide as well as bortezomib. Thus there remains a continued need to identify newer agents to maintain long term disease control in these patients.

Thalidomide and its immune-modulatory analogue lenalidomide have clinical activity in myeloma. Pomalidomide, a thalidomide analogue, is an immunomodulatory agent that displays similar anti-angiogenic activity, but far greater anti-proliferative and immunomodulatory activity, compared to the parent drug. Pomalidomide and lenalidomide have been shown to possess very similar pharmacological properties in vitro, including anti-angiogenic, immunomodulatory and anti-proliferative properties. However a unifying molecular mechanism for these diverse effects has been elusive. Pomalidomide and lenalidomide have significantly greater capacity for enhanced costimulation, leading to enhanced activation of innate and adaptive immune cells compared to Thalidomide. Recent studies have yielded the surprising finding that these agents can mediate rapid biologic effects on human monocytes and T cells in culture leading to activation of ras homolog gene family, member A (RhoA) GTPases, and enhanced actin polymerization. Changes in actin cytoskeleton may also contribute to the capacity to these drugs to enhance the formation of immune synapses, Pomalidomide has also been shown to stimulate antibody-dependent cytotoxic T-cell activity (ADCC) in preclinical models.

At tolerated doses (MTD = 2 mg per day (QD) and 5 mg every other day (QOD), pomalidomide has been shown to be active in subjects with relapsed or refractory multiple myeloma (study CC-4047-00-001). In 45 subjects who received doses of pomalidomide ranging, by cohort, up to 10 mg daily, the most commonly occurring dose-limiting toxicity (DLT) was reversible neutropenia. As with other immunomodulatory drugs (IMiDs) administered to subjects receiving concomitant systemic steroids, deep vein thrombosis (DVT) was seen (in 1 subject each in this study and in its subsequent named patient supply rollover program).

Recently, preliminary efficacy and safety data from an ongoing phase II study, led by Martha Lacy at Mayo Clinic, were published. Sixty patients with relapsed or refractory multiple myeloma were enrolled. Pomalidomide (CC-4047) was given orally at a dose of 2 mg daily on days 1-28 of a 28-day cycle and dexamethasone was given orally at a dose of 40 mg daily on days 1, 8, 15, 22 of each cycle. Patient also received aspirin 325 mg once daily for thromboprophylaxis. The study endpoints were the response rate in patients taking pomalidomide plus dexamethasone including patients with lenalidomide resistant refractory multiple myeloma, and safety of pomalidomide plus dexamethasone. Responses were recorded using the criteria of the International Myeloma Working Group. Thirty eight patients achieved objective response (63%) including complete response (CR) in 3 patients (5%), very good partial response (VGPR) in 17 patients (28%), and partial response (PR) in 18 patients (30%). The CR + VGPR rate was 33%. Grade 3 or 4 hematologic toxicity occurred in 23 patients (38%) and consisted of anemia in three patients (5%), thrombocytopenia in two patients (3%) and neutropenia in 21 (35%). Among those that developed grade 3/4 neutropenia, all first experienced the neutropenia in cycle 1-3; no new patients experienced grade 3/4 neutropenia in cycle 4 or later. The most common non-hematological grade 3/4 toxicities were fatigue (17%) and pneumonia (8%). Other grade 3/4 non-hematological toxicities that occurred in less than 5% included diarrhea, constipation, hyperglycemia, and neuropathy. One patient (1.6%) had a thromboembolic event of deep vein thrombosis.

Another dosing regimen for Pomalidomide involved 21/28 day dosing, as in the current dosing regimen for Lenalidomide. In this trial the recommended dose for phase II testing was determined to be 4 mg, 21/28 d. Clinical response (greater than or equal to a partial response (PR)) was observed in 7/25 (28%) patients. While both regimens seem to be clinically active, it is unclear at present as to which regimen leads to greater immune activation or clinical activity.

In addition to MM, pre-clinical data and the prior experience with thalidomide and lenalidomide in the treatment of patients with myelofibrosis with myeloid metaplasia (MMM) provided the rationale for the use of pomalidomide in patients with MMM. This is further supported by the results of a Celgene sponsored trial (MMM-001) which indicated that pomalidomide therapy at 0.5 mg or 2 mg/day +/- an abbreviated course of prednisone is well tolerated in patients with myelofibrosis and active in the treatment of anemia.

However, these studies did not monitor proximate pharmacodynamic events (such as might occur within hours of drug exposure), and link these to downstream effects, including clinical activity and toxicity. Our hypothesis is that the proximate effects of these drugs (including drug induced changes in F-actin) and early phosphorylation events will be sensitive and quantitative surrogates of subsequent effects including activation of tumor antigen specific T cells as well as innate immune cells. Understanding the correlation between pharmacodynamics of these effects with downstream activation using quantitative assays will facilitate rational development of these agents as immunomodulatory drugs in diverse settings and may also allow optimization of drug delivery to both reduce potential toxicity, and enhance efficacy.

Continuous Versus Intermittent Dosing Regimens for Pomalidomide in Relapsed/Refractory Multiple Myeloma

Clinical and Pharmacodynamic Comparison of Continuous Versus Intermittent Dosing Regimens for Pomalidomide in Relapsed/Refractory Multiple Myeloma

All partial and complete responses must be confirmed with another efficacy assessment in no less than 4 weeks apart.

Correlation to be determined upon completion of study treatment

Research bone marrow aspirate is obtained to assess response (optional, but recommended), and to document complete remission, if applicable. Correlation to be determined upon completion of study treatment

Celgene Corporation

Yale University

Pomalidomide: Comparison of different dosages and schedules of drug

Pomalidomide 4 mg/d on 21 Days/28 Day Cycle

Pomalidomide 2 mg/d on 28 Days/28 Day Cycle

Total

Age, Continuous

Sex: Female, Male

Immunoglobulin G (IgG)

Immunoglobulin A (IgA)

Light chain only

Immunoglobulin Heavy chain (IgH) type

kappa

lambda

Immunoglobulin Light chain (IgL) type

serum beta 2 microglobulin

serum albumin

lines of prior therapy

missing

Deletion of chromosome 17p

Chromosome 1q abnormalities

Monosomy 13 on molecular cytogenics or deletion of 13q on fluorescence in situ hybridization (FISH) cytogenics

Deletion chromosome 13

Lenalidomide (Len) as most recent therapy

Resistance to prior therapy-Len refractory

Resistance to prior therapy-Len+bortezomib refractory

Percentage of Participants With Response, Analyzed Per International Myeloma Working Group Response Criteria

cycle 4

cycle 6

cycle 8

cycle 10

cycle 12

cycle 14

N/A: data were not collected on this outcome; initial F actin polymerization assay was unreliable and not reproducible; hence, this outcome could not be pursued.

To Compare the Effect of Continuous Versus Intermittent Regimens on F Actin Polymerization in Peripheral Blood Mononuclear Cells and Activation of Tumor Antigen-specific T Cells, as Well as Innate Lymphocytes (Natural Killer or Natural Killer T Cells).

The actin polymerization assay that was to be used for this outcome was not reproducible and data were not analyzed.

To Correlate Drug Induced Changes in F Actin Polymerization With Adverse Effects and Clinical Responses.

The actin polymerization assay that was to be used for this outcome was not reproducible; hence, the cytokine profile of actin polymerized cells could not be pursued. Data were not analyzed.

To Correlate Drug Induced Changes in F Actin With Cytokine Profile.

Overall Study

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Symptoms and General Pathology

Kidney Diseases

Renal Insufficiency

Renal Insufficiency, Chronic

Urologic Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Male Urogenital Diseases

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Anti-Infective Agents

Anti-Inflammatory Agents

Antiemetics

Gastrointestinal Agents

Thalidomide

Dexamethasone

Bendamustine Hydrochloride

Bortezomib

Dexamethasone acetate

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Antineoplastic Agents, Alkylating

Alkylating Agents

Immunosuppressive Agents

Anti-Bacterial Agents

Bortezomib, Bendamustine and Dexamethasone

Thalidomide, Bendamustine and Dexamethasone

1.3 mg/m2 subcutaneously\* days 1, 4, 8 and 11 of each cycle. Number of cycles: Four 21 day cycles (participants not suitable for ASCT (autologous stem cell transplant) will continue up to 6 cycles on the treatment regimen to which they were randomised).

\*intravenous infusion available in case of patient intolerance to subcutaneous bortezomib

100 mg daily orally, preferably at night, days 1-21 of each cycle. Four 21 day cycles (participants not suitable for ASCT will continue up to 6 cycles on the treatment regimen to which they were randomised)

60 mg/m2 i.v. days 1 and 8 of each cycle. Four 21 day cycles (participants not suitable for ASCT will continue up to 6 cycles on the treatment regimen to which they were randomised)

Bendamustine

40mg orally days 1-2, 4-5, 8-9 and 11-12 of each cycle

Karthik Ramasamy

The purpose of this study is to compare the effectiveness of bortezomib versus thalidomide in reducing free light chains in the blood of myeloma patients. In addition participants will receive bendamustine (chemotherapy) and dexamethasone (steroids), which increase the effectiveness of both bortezomib and thalidomide. The trial will also study whether an earlier reduction of free light chains increases the chances of the kidneys recovering.

Renal impairment is a life threatening condition of myeloma. 20-25% of patients will present at diagnosis with renal dysfunction. Outcome is poor due to high early mortality, with 28% of newly diagnosed myeloma patients in myeloma trials with renal failure not surviving beyond 100 days, compared with 10% overall.

This study aims to establish:

1. Whether proteosomal inhibition (bortezomib) or immunomodulatory (thalidomide) based therapy achieves threshold reduction of serum free light chains (sFLCs) in a significant majority of patients.
2. Whether sFLC response to the first 2 cycles (early responder) predicts haematological and renal response to the next 2 cycles of therapy.
3. An early time point for assessment of sFLC reduction as a biomarker for response.

Participants will be stratified by age and chronic kidney disease (CKD) stage to receive either bortezomib, bendamustine and dexamethasone (BBD) or thalidomide, bendamustine and dexamethasone (BTD).

Optimising Renal Outcome in Myeloma Renal Failure

A Study of Thalidomide, Bendamustine and Dexamethasone (BTD) Versus Bortezomib, Bendamustine and Dexamethasone (BBD) in Patients With Renal Failure Defined as a GFR Below 30 Mls/Min

The EQ-5D-3L descriptive system comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension is scored on a scale of 1 to 3: 1 (no problems), 2 (some problems), and 3 (extreme problems). Higher score equates to a worse outcome.

As stated in the official EQ-5D user guide, patient responses to the 5 questions were converted into a single index value as per Dolan P (1997). Modeling valuations for EuroQol health states. Med Care 35(11):1095-108. These index values, with country specific value sets, facilitate the calculation of quality-adjusted life years (QALYs) that are used to inform economic evaluations of health care interventions. In the UK, the values range from -0.594 to +1.

Janssen-Cilag Ltd.

Bloodwise

University of Warwick

University of Birmingham

Oxford University Hospitals NHS Trust

Bortezomib, Bendamustine and Dexamethasone

Bortezomib: 1.3 mg/m2 subcutaneously\* days 1, 4, 8 and 11 of each cycle. Number of cycles: Four 21 day cycles (participants not suitable for ASCT (autologous stem cell transplant) will continue up to 6 cycles on the treatment regimen to which they were randomised).

\*intravenous infusion available in case of patient intolerance to subcutaneous bortezomib

Bendamustine: 60 mg/m2 i.v. days 1 and 8 of each cycle. Four 21 day cycles (participants not suitable for ASCT will continue up to 6 cycles on the treatment regimen to which they were randomised)

Dexamethasone: 40mg orally days 1-2, 4-5, 8-9 and 11-12 of each cycle

Arm A (BBD)

Thalidomide, Bendamustine and Dexamethasone

Thalidomide: 100 mg daily orally, preferably at night, days 1-21 of each cycle. Four 21 day cycles (participants not suitable for ASCT will continue up to 6 cycles on the treatment regimen to which they were randomised)

Bendamustine: 60 mg/m2 i.v. days 1 and 8 of each cycle. Four 21 day cycles (participants not suitable for ASCT will continue up to 6 cycles on the treatment regimen to which they were randomised)

Dexamethasone: 40mg orally days 1-2, 4-5, 8-9 and 11-12 of each cycle

Arm B (BTD)

≤70 years

>70 years

Age, Customized

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

United Kingdom

Region of Enrollment

Richard Brouwer

The primary endpoint of serum free light chain response was assessed in 30 patients where samples were available at screening and the end of two cycles of trial treatment.

Number of Participants With >50% Reduction From Baseline in Serum Free Light Chain

Renal response in accordance with IMWG criteria was assessed in 20 patients with eGFR and creatinine clearance data recorded at screening and at the end of four cycles of trial treatment.

Number of Participants With Different Renal Responses to Treatment

Serious adverse events

Adverse events

Haematological and Non-haematological Toxicity in Both Treatment Arms

Overall Survival

Partial response

Minor response

No repsonse

Renal Response After Two Cycles of Trial Treatment

Baseline

1 month FU

Quality of Life Measured by the EQ-5D-3L Questionnaire at Baseline and 1 Month Follow up

Respiratory Tract (Lung and Bronchial) Diseases

Digestive System Diseases

Lung Neoplasms

Head and Neck Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Patients with cancer of the head and neck, thorax and upper gastrointestinal tract, who are receiving or may receive treatments known or hypothesized to have an immunomodulatory antitumor effect.

Collection of tumor, blood, lymph nodes, white blood cells, mouth cells (buccal smears) scraped from the inside of your cheek, urine, saliva, or other tissue samples.

Collection of biological specimens

Patrick Forde, MD

Peggy Fitzpatrick, RN

This research is being done to collect and store biological specimens (biospecimens) from people with cancer, regardless of tumor type, who are receiving treatments known or thought to have an effect on the immune system.

The goal of this discovery and exploratory study is to:

* Understand changes in the immune system associated with various cancer treatments, in order to better design new therapies or tests to predict how these treatments might work.
* Identify risk factors for those who go on to develop side effects from immunotherapy.

Participants may be asked to:

* Donate samples of tumor, blood, lymph nodes, white blood cells, mouth cells (buccal smears) scraped from the inside of participant's cheek, urine, saliva, or other tissue samples.
* Complete questionnaires about immunotherapy side effects at baseline and with follow-up appointments.
* Undergo knee x-rays.
* Allow the use of demographic and clinical information.

The Immunobiology Blood and Tissue Collection of Upper Aerodigestive Malignancies Protocol is a discovery and exploratory protocol that will enable the investigators to obtain and archive biological specimens from patients with cancer of the head and neck, thorax and upper gastrointestinal tract, who are receiving or may receive treatments known or hypothesized to have an immunomodulatory antitumor effect. The investigators aim to conduct immunologic studies across tumor types and treatment modalities in order to accomplish the following:

1. Gain mechanistic insights into the potential influence of various forms of cancer therapy on antitumor immunity, including but not limited to chemotherapies, kinase inhibitors, angiogenesis inhibitors, immune-modulating monoclonal antibodies, cellular immune therapies and radiation therapy.
2. Define new tumor antigens and the tumor antigens' relevance to disease biology, and correlate antigen expression with immune responses and disease outcomes.
3. Evaluate potential immune-related prognostic or treatment response indicators.
4. Assess the immunologic features of pre-malignant lesions (e.g., atypical or dysplastic nevi, dysplastic bronchial epithelium, colonic adenomas), and compare these features to features of invasive cancers.
5. Investigate the immunobiology of neoadjuvant and adjuvant cancer therapies, including but not limited to cancer vaccines.
6. Develop protein-, RNA-, and DNA-based blood markers to monitor tumor burden and predict and detect tumor relapse.
7. Evaluate the causative mechanisms of immune-related toxicities in patients receiving cancer therapy with immune checkpoint blockade.
8. Characterize factors and molecular pathways in the tumor immune microenvironment that lead to immune suppression, tolerance to tumor antigens, and cancer progression.
9. Understand the epidemiology of and risk factors for particular immune related adverse events (irAEs) including inflammatory arthritis, sicca syndrome and myositis

To support the above research aims, biological specimens obtained and processed in the individual laboratories of the co-investigators will be linked by a centralized demographic database, allowing for the retrieval of information regarding specimen characteristics (e.g., tumor type, treatment exposure, date of specimen retrieval, anatomic site of biopsy, biopsy procedure) and clinical outcomes. Participants starting on immune checkpoint inhibitors will complete a survey when the participants enroll on study to assess for potential risk factors for irAE development. Participants will also undergo knee radiographs to evaluate for osteoarthritis, baseline survey for personal and family historical risk factors, and serial surveys designed to screen for development of irAEs This information will be correlated with the results of exploratory scientific analyses conducted in the laboratories of the co-investigators. Hypotheses generated from this work are expected to support future hypothesis-driven scientific investigations and clinical trial development.

* Tissue Sample Acquisition:

  * Excess material collected in the course of therapeutic procedures that are clinically indicated; or
  * New biopsies performed for research purposes (e.g., a palpable subcutaneous nodule, or a lymph node that is accessible by ultrasound or computed tomography scan guidance under local anesthesia).
* Blood Sample Acquisition: A peripheral blood sample will be collected from each participating subject for the isolation and cryopreservation of viable peripheral blood mononuclear cells, serum, and plasma.
* Leukapheresis: patients may undergo pheresis for the purpose of collecting large numbers of leukocytes for research purposes.
* Buccal smears
* Bronchoscopy: Endobronchial brushings +/- biopsies
* Nasal Epithelium Collection
* Expectorated Sputum Collection

Immunobiology Blood and Tissue Collection of Upper Aerodigestive Malignancies

This is a clinic based registry of cancer therapy data from participants to be collected over time.

This is a virtual tissue bank containing biological specimens from participants collected over time.

Stand Up To Cancer

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Continuous Versus Intermittent Dosing Regimens for Pomalidomide in Relapsed/Refractory Multiple Myeloma	NCT01319422	Multiple Myelom...	Pomalidomide	18 Years -	Yale University
Continuous Versus Intermittent Dosing Regimens for Pomalidomide in Relapsed/Refractory Multiple Myeloma	NCT01319422	Multiple Myelom...	Pomalidomide	18 Years -	Yale University
Optimising Renal Outcome in Myeloma Renal Failure	NCT02424851	Multiple Myelom... Chronic Kidney ...	Bortezomib Thalidomide Bendamustine Dexamethasone	18 Years -	Oxford University Hospitals NHS Trust
Immunobiology Blood and Tissue Collection of Upper Aerodigestive Malignancies	NCT05995821	Head and Neck C... Lung Cancer Gastrointestina...	Collection of b...	18 Years -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Continuous Versus Intermittent Dosing Regimens for Pomalidomide in Relapsed/Refractory Multiple Myeloma	NCT01319422	Multiple Myelom...	Pomalidomide	18 Years -	Yale University

Spots Global Cancer Trial Database for immunomodulatory