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KRDI in Transplant-Eligible MM

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04430894
Recruitment Status : Recruiting
First Posted : June 12, 2020
Last Update Posted : September 2, 2020
Sponsor:
Collaborators:
Amgen
Sanofi
Information provided by (Responsible Party):
Elizabeth O'Donnell, Massachusetts General Hospital

Brief Summary:

This research study is testing the efficacy of an experimental drug combination for people with newly diagnosed multiple myeloma that are eligible for a stem cell transplant.

The names of the study drugs involved in this study are:

  • Carfilzomib
  • Isatuximab
  • Lenalidomide
  • Dexamethasone

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Carfilzomib Drug: Isatuximab Drug: Lenalidomide Drug: Dexamethasone Phase 2

Detailed Description:

This is a phase II study to evaluate the efficacy of once weekly carfilzomib, lenalidomide, dexamethasone, and isatuximab (KRDI) in patients with newly diagnosed, transplant-eligible multiple myeloma. The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. The study treatment portion of this study is comprised of an induction phase and a maintenance phase.

  • Induction Phase :

    • All participants will receive the same study drugs (carfilzomib, isatuximab, lenalidomide, and dexamethasone) for up to 8 cycles. Each cycle is 28 days in length.
    • All participants will perform stem cell collection after 4 cycles of therapy. Based on the recommendation participants may or may not proceed to an autologous stem cell transplant (SCT) as part of induction therapy.
  • Maintenance Phase: During maintenance, participants will receive the study treatment for up to two years after induction until progressive disease or unacceptable toxicity

It is expected that about 50 people will take part in this research study.

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug combination to learn whether the drug combination works in treating a specific disease.

"Investigational" means that the drug combination is being studied.

The U.S. Food and Drug Administration (FDA) has approved carfilzomib or isatuximab as a treatment for relapsed/refractory multiple myeloma.

The FDA has also approved lenalidomide and dexamethasone as a treatment option for transplant-eligible multiple myeloma.

However, the FDA has not approved the combination of isatuximab, carfilzomib, lenalidomide, and dexamethasone as an approved regimen. The combination is considered to be investigational for the treatment of individuals with newly diagnosed multiple myeloma.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Once Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Isatuximab in Newly Diagnosed, Transplant-Eligible Multiple Myeloma
Actual Study Start Date : July 10, 2020
Estimated Primary Completion Date : September 30, 2021
Estimated Study Completion Date : September 30, 2021


Arm Intervention/treatment
Experimental: Induction
  • All participants will receive the same study drugs up to 8 cycles. Carfilzomib, Isatuximab, Lenalidomide, Dexamethasone: Each cycle is 28 days in length.
  • Stem cell collection after 4 cycles of therapy. Based on the recommendation participants may or may not proceed to an autologous stem cell transplant (SCT) as part of induction therapy.

    • Up Front Autologous Stem Cell Transplant:

      --- 4 cycles of treatment, followed by stem cell collection, high-dose chemotherapy, and autologous SCT followed by 2 additional cycles of therapy (called consolidation) and then maintenance.

    • Deferring Stem Cell Transplant:

      • Deferring SCT following collection: 4 cycles of treatment, followed by stem cell collection followed by 4 additional cycles of therapy and then maintenance
Drug: Carfilzomib
  • Induction: protocol determine dose,via IV on 3 days per cycle up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination
  • Maintenance: protocol determine dose,via IV on 2 days per cycle- Maintenance Cycle until progressive disease (PD) or unacceptable toxicity
Other Name: Kyprolis

Drug: Isatuximab
  • Induction: At predetermined dose, via IV up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination:

    -- Cycles 1 and 2 once per week, Cycles 3-4 every other week, Cycles 5 and 6 every other week, Cycles 7 and 8 once every 4 weeks.

  • Maintenance: At predetermined dose, via IV, once per cycle, Maintenance Cycle until progressive disease (PD) or unacceptable toxicity
Other Name: Sarclisa

Drug: Lenalidomide
- Induction Predetermined Dose, oral, days 1-21 of up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: At predetermined dose, oral days 1-21 per cycle until progressive disease (PD) or unacceptable toxicity
Other Name: REVLIMID

Drug: Dexamethasone
Induction: Predetermined dosage, oral, Predetermined times per cycle up to 8 cycles dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: orally or IV will be administered as a preinfusion medication prior to isatuximab dosing
Other Name: Decadron

Experimental: Maintenance-High Risk

Experimental: Maintenance The treatment participants will receive for maintenance will be based on the biological features (or cytogenetics) of participants myeloma and categorized into two groups: Standard-risk and High Risk.

High Risk: All participants will receive study treatment for up to two years after induction until progressive disease (PD) or unacceptable toxicity

  • Lenalidomide
  • Carfilzomib
  • Isatuximab
Drug: Carfilzomib
  • Induction: protocol determine dose,via IV on 3 days per cycle up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination
  • Maintenance: protocol determine dose,via IV on 2 days per cycle- Maintenance Cycle until progressive disease (PD) or unacceptable toxicity
Other Name: Kyprolis

Drug: Isatuximab
  • Induction: At predetermined dose, via IV up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination:

    -- Cycles 1 and 2 once per week, Cycles 3-4 every other week, Cycles 5 and 6 every other week, Cycles 7 and 8 once every 4 weeks.

  • Maintenance: At predetermined dose, via IV, once per cycle, Maintenance Cycle until progressive disease (PD) or unacceptable toxicity
Other Name: Sarclisa

Drug: Lenalidomide
- Induction Predetermined Dose, oral, days 1-21 of up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: At predetermined dose, oral days 1-21 per cycle until progressive disease (PD) or unacceptable toxicity
Other Name: REVLIMID

Drug: Dexamethasone
Induction: Predetermined dosage, oral, Predetermined times per cycle up to 8 cycles dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: orally or IV will be administered as a preinfusion medication prior to isatuximab dosing
Other Name: Decadron

Experimental: Maintenance- Standard Risk

The treatment participants will receive for maintenance will be based on the biological features (or cytogenetics) of participants myeloma and categorized into two groups: Standard-risk and High Risk

  • Lenalidomide - Standard of care All participants will receive study treatment for up to two years after induction until progressive disease (PD) or unacceptable toxicity
Drug: Lenalidomide
- Induction Predetermined Dose, oral, days 1-21 of up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: At predetermined dose, oral days 1-21 per cycle until progressive disease (PD) or unacceptable toxicity
Other Name: REVLIMID




Primary Outcome Measures :
  1. Complete Response (CR + stringent CR) rate [ Time Frame: 112 Days ]
    International Myeloma Working Group (IMWG) Uniform Response criteria after 4 cycles of KRDI.


Secondary Outcome Measures :
  1. Overall Response Rate [ Time Frame: 24 Months ]
    Overall response rate will be percent of patients who achieve at least partial response (PR).

  2. Minimal residual disease (MRD) Rate [ Time Frame: 112 Days (4 Cycles) ]
    Will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA)

  3. Minimal residual disease (MRD) Rate [ Time Frame: 168 Days (6 cycles, upfront transplant) ]
    Will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA)

  4. Minimal residual disease (MRD) Rate [ Time Frame: 224 Days (8 cycles transplant-deferred) ]
    Will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA)

  5. Minimal residual disease (MRD) Rate [ Time Frame: 24 Months ]
    Will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA)

  6. Progression Free Survival [ Time Frame: time from first dose of study treatment to the first documentation of PD or death from any cause during study up to 3 years ]
    Kaplan-Meier curves will be used to characterize the time-to-event outcomes

  7. Overall Survival [ Time Frame: First dose of study treatment to death from any cause up to 3 years ]
    Kaplan-Meier curves will be used to characterize the time-to-event outcomes

  8. Number of Participants with Treatment-Related Adverse Events as NCI CTCAE Version 5.0 severity grades. [ Time Frame: From the time of first treatment to treatment discontinuation (30 days after last dose) up to 3 years ]
    NCI CTCAE Version 5.0 severity grades.

  9. Complete Response rate (Transplant) [ Time Frame: 168 Days ]
    IMWG Uniform Response Criteria Complete response (CR + stringent CR) rate after 6 cycles in patients who undergo transplant

  10. Complete Response rate (Transplant Deferred) [ Time Frame: 224 Days ]
    IMWG Uniform Response Criteria Complete response (CR + stringent CR) rate after 8 cycles in patients who do not undergo transplant

  11. Complete Response rate (All ) [ Time Frame: 24 Months ]
    IMWG Uniform Response Criteria


Other Outcome Measures:
  1. Body composition [ Time Frame: 168 ]
    Total lean mass (cm^2), extremity lean mass (cm^2), total fat (cm^2) and trunk fat mass (cm^20, as well as visceral adipose tissue mass (cm^2) will be quantified using Hologic APEX 3.1 software (Hologic) after 6 cycles of treatment (upfront transplant)

  2. Body composition [ Time Frame: 224 ]
    Total lean mass (cm^2), extremity lean mass (cm^2), total fat (cm^2) and trunk fat mass (cm^20, as well as visceral adipose tissue mass (cm^2) will be quantified using Hologic APEX 3.1 software (Hologic) after 6 cycles of treatment (transplant-deferred)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subject must be at least 18 years of age.
  • Subject must have documented multiple myeloma satisfying the CRAB criteria and measurable disease defined as:

    • Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy-proven Plasmacytoma.
    • Measurable disease as defined by any of the following:
    • IgG myeloma: Serum monoclonal paraprotein (M-protein) level ≥.5 g/dL or urine M-protein level ≥200 mg/24 hours; or
    • IgA, IgM, or IgD multiple myeloma: serum M-protein level ≥0.25 g/dL or urine M-protein level ≥200 mg/24 hours; or
    • Light chain multiple myeloma: Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.
    • Sixty percent or greater clonal plasma cells on bone marrow examination.
    • Serum involved / uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved free light chain is at least 100 mg/L (a patient's "involved" free light chain - either kappa or lambda - is the one that is above the normal reference range; the uninvolved light chain is the one that typically is in, or below, the normal range).
    • More than one focal lesion on magnetic resonance image (MRI) that is at least 5 mm or greater in size.
  • Newly diagnosed and considered candidate for high-dose chemotherapy with stem cell transplant.
  • Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.
  • Subject must have pretreatment clinical laboratory values meeting the following criteria during the Screening Phase:

    • hemoglobin ≥ 7.5 g/dL (≥ mmol/L; prior RBC transfusion or recombinant human erythropoietin use is permitted);
    • absolute neutrophil count ≥1.0 x 109/L (granulocyte colony stimulating factor [GCSF] use is permitted);
    • platelet count ≥70 x 109/L for subjects in whom <50% of bone marrow nucleated cells are plasma cells; otherwise platelet count >50 × 109/L (transfusions are not permitted to achieve this minimum platelet count)
    • aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN);
    • alanine aminotransferase (ALT) ≤2.5 x ULN;
    • total bilirubin ≤2.0 x ULN, except in subjects with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin ≤2.0 x ULN)
    • creatinine clearance ≥30 mL/min
    • corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L); or free ionized calcium <6.5 mg/dL (<1.6 mmol/L).
  • Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device [IUD], hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
  • A man who is sexually active with a woman of childbearing potential must agree to use a latex or synthetic condom, even if they had a successful vasectomy. All men must also not donate sperm during the study, for 4 weeks after the last dose of lenalidomide, for 90 days after the last dose of carfilzomib, and for 4 months after the last dose of isatuximab.
  • A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 10 to 14 days prior to dosing and the second within 24 hours prior to dosing.
  • Each subject (or their legally acceptable representative) must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF.

Exclusion Criteria:

  • Any potential subject who meets any of the following criteria will be excluded from participating in the study.
  • Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma. Monoclonal gammopathy of undetermined significance is defined by presence of serum M-protein <3 g/dL; absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the M-protein; and (if determined) proportion of plasma cells in the bone marrow of 10% or less. Smoldering multiple myeloma is defined as asymptomatic MM with absence of related organ or tissue impairment end organ damage.
  • Subject has a diagnosis of Waldenström's disease, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions
  • Subject has prior or current systemic therapy or SCT for MM, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment.
  • Subject has a history of malignancy (other than MM) within 5 years before the date of enrollment (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 5 years).
  • Subject has had radiation therapy within 14 days of enrollment.
  • Subject has had plasmapheresis within 28 days of enrollment.
  • Subject is exhibiting clinical signs of meningeal involvement of MM.
  • Subject has known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume [FEV] in 1 second <60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years (intermittent asthma is allowed). Subjects with known or suspected COPD or asthma must have a FEV1 test during screening.
  • Subject is known to be seropositive for history of human immunodeficiency virus (HIV) or known to have active hepatitis B or hepatitis C.
  • Subject has any concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.
  • Subject has clinically significant cardiac disease, including:

    • myocardial infarction within 1 year before enrollment, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV;
    • uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4 Grade ≥2) or clinically significant ECG abnormalities;
    • screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >470 msec.
    • uncontrolled hypertension
  • Subject has known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or IB) or known sensitivity to mammalian-derived products.
  • Subject has plasma cell leukemia (according to World Health Organization [WHO] criterion: ≥20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 109/L) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
  • Subject is known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder). Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol specified assessments.
  • Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study within 30 days after the last dose of lenalidomide or carfilzomib, or within 4 months after the last dose of isatuximab. Or, subject is a man who plans to father a child while enrolled in this study, within 4 weeks after the last dose of lenalidomide, within 90 days of the last dose of carfilzomib, or within 4 months after the last dose of isatuximab.
  • Subject has had major surgery within 2 weeks before enrollment or has not fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study. Kyphoplasty or vertebroplasty is not considered major surgery.
  • Subject has received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before enrollment or is currently enrolled in an interventional investigational study.
  • Subject has contraindications to required prophylaxis for deep vein thrombosis and pulmonary embolism.
  • Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs.
  • Peripheral neuropathy ≥ Grade 2 on clinical examination during the screening period.
  • Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobartital), or use of Ginkgo biloba, St. John's wort within 14 days before the first dose of study treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04430894


Contacts
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Contact: Elizabeth O'Donnell, MD ekodonnell@partners.org ekodonnell@partners.org

Locations
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United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Elizabeth O'Donnell, MD    617-724-4000    ekodonnell@partners.org   
Principal Investigator: Elizabeth O'Donnell, MD         
Beth Israel Deaconess Medical Center Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Jacalyn Rosenblatt, MD    617-667-9920    jrosenb1@bidmc.harvard.edu   
Principal Investigator: Jacalyn Rosenblatt, MD         
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Omar Nadeem, MD    617-632-3823    Omar_nadeem@dfci.harvard.edu   
Principal Investigator: Omar Nadeem, MD         
Sponsors and Collaborators
Massachusetts General Hospital
Amgen
Sanofi
Investigators
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Principal Investigator: Elizabeth O'Donnell, MD Massachusetts General Hospital
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Responsible Party: Elizabeth O'Donnell, Principal Investigator, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT04430894    
Other Study ID Numbers: 19-568
First Posted: June 12, 2020    Key Record Dates
Last Update Posted: September 2, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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 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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Data can be shared no earlier than 1 year following the date of publication
Access Criteria: MGH - Contact the Partners Innovations team at http://www.partners.org/innovation

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Elizabeth O'Donnell, Massachusetts General Hospital:
Multiple Myeloma
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Lenalidomide
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Immunologic Factors
Angiogenesis Inhibitors
Angiogenesis Modulating Agents