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A BIOmarker Driven Trial With Nivolumab and Ipilimumab or VEGFR tKi in Naïve Metastatic Kidney Cancer (BIONIKK)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02960906
Recruitment Status : Completed
First Posted : November 10, 2016
Last Update Posted : April 26, 2021
Sponsor:
Information provided by (Responsible Party):
Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie

Brief Summary:

Disease and Stage: naïve metastatic kidney cancer.

A multicenter, randomized, a Phase 2 BIOmarker driven trial with Nivolumab and Ipilimumab or VEGFR tKi in naïve metastatic Kidney cancer


Condition or disease Intervention/treatment Phase
Clear Cell Metastatic Renal Cell Carcinoma Drug: Nivolumab Drug: Ipilimumab Drug: Pazopanib Drug: Sunitinib Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 BIOmarker Driven Trial With Nivolumab and Ipilimumab or VEGFR tKi in Naïve Metastatic Kidney Cancer
Actual Study Start Date : May 31, 2017
Actual Primary Completion Date : February 15, 2021
Actual Study Completion Date : February 15, 2021


Arm Intervention/treatment
Experimental: ccRCC molecular subgroup 1: 1A

ccRCC molecular subgroup 1 -> randomisation: subjects with ccRCC1 treated with nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Drug: Nivolumab

For Arms 1A and 4A:

Nivolumab alone administered IV over 60 minutes at 240 mg every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

For Arms 1B, 2B, 3B and 4B:

Nivolumab administered IV over 60 minutes at 3 mg/kg combined with ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 60 minutes at 240 mg every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Other Names:
  • BMS-936558
  • Opdivo

Experimental: ccRCC molecular subgroup 1: 1B

ccRCC molecular subgroup 1 -> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Drug: Nivolumab

For Arms 1A and 4A:

Nivolumab alone administered IV over 60 minutes at 240 mg every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

For Arms 1B, 2B, 3B and 4B:

Nivolumab administered IV over 60 minutes at 3 mg/kg combined with ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 60 minutes at 240 mg every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Other Names:
  • BMS-936558
  • Opdivo

Drug: Ipilimumab

For Arms 1B, 2B, 3B and 4B:

Ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks combined with Nivolumab administered IV over 60 minutes at 3 mg/kg for 4 doses until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Other Names:
  • YERVOY
  • BMS-734016

Experimental: ccRCC molecular subgroup 4: 4A

ccRCC molecular subgroup 4 -> randomisation: subjects with ccRCC1 treated with nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Drug: Nivolumab

For Arms 1A and 4A:

Nivolumab alone administered IV over 60 minutes at 240 mg every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

For Arms 1B, 2B, 3B and 4B:

Nivolumab administered IV over 60 minutes at 3 mg/kg combined with ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 60 minutes at 240 mg every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Other Names:
  • BMS-936558
  • Opdivo

Experimental: ccRCC molecular subgroup 4: 4B

ccRCC molecular subgroup 4 -> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Drug: Nivolumab

For Arms 1A and 4A:

Nivolumab alone administered IV over 60 minutes at 240 mg every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

For Arms 1B, 2B, 3B and 4B:

Nivolumab administered IV over 60 minutes at 3 mg/kg combined with ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 60 minutes at 240 mg every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Other Names:
  • BMS-936558
  • Opdivo

Drug: Ipilimumab

For Arms 1B, 2B, 3B and 4B:

Ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks combined with Nivolumab administered IV over 60 minutes at 3 mg/kg for 4 doses until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Other Names:
  • YERVOY
  • BMS-734016

Experimental: ccRCC molecular subgroup 2: 2C
ccRCC molecular subgroup 2 -> randomisation: TKI (sunitinib 50mg daily or Pazopanib 800mg daily) according to investigator's choice until disease progression, unacceptable toxicity or other reasons specified in the protocol.
Drug: Pazopanib

For Arms 2C and 3C (TKI pazopanib or sunitinib):

Pazopanib 800 mg orally QD until disease progression, unacceptable toxicity or other reasons specified in the protocol

Other Name: Votrient

Drug: Sunitinib

For Arms 2C and 3C (TKI pazopanib or sunitinib):

Sunitinib 50 mg orally QD until disease progression, unacceptable toxicity or other reasons specified in the protocol

Other Name: Sutent

Experimental: ccRCC molecular subgroup 2: 2B

ccRCC molecular subgroup 2 -> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Drug: Nivolumab

For Arms 1A and 4A:

Nivolumab alone administered IV over 60 minutes at 240 mg every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

For Arms 1B, 2B, 3B and 4B:

Nivolumab administered IV over 60 minutes at 3 mg/kg combined with ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 60 minutes at 240 mg every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Other Names:
  • BMS-936558
  • Opdivo

Drug: Ipilimumab

For Arms 1B, 2B, 3B and 4B:

Ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks combined with Nivolumab administered IV over 60 minutes at 3 mg/kg for 4 doses until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Other Names:
  • YERVOY
  • BMS-734016

Experimental: ccRCC molecular subgroup 3: 3B

ccRCC molecular subgroup 3 -> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Drug: Nivolumab

For Arms 1A and 4A:

Nivolumab alone administered IV over 60 minutes at 240 mg every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

For Arms 1B, 2B, 3B and 4B:

Nivolumab administered IV over 60 minutes at 3 mg/kg combined with ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 60 minutes at 240 mg every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Other Names:
  • BMS-936558
  • Opdivo

Drug: Ipilimumab

For Arms 1B, 2B, 3B and 4B:

Ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks combined with Nivolumab administered IV over 60 minutes at 3 mg/kg for 4 doses until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Other Names:
  • YERVOY
  • BMS-734016

Experimental: ccRCC molecular subgroup 3: 3C
ccRCC molecular subgroup 3 -> randomisation: TKI (sunitinib 50mg daily or Pazopanib 800mg daily) according to investigator's choice until disease progression, unacceptable toxicity or other reasons specified in the protocol.
Drug: Pazopanib

For Arms 2C and 3C (TKI pazopanib or sunitinib):

Pazopanib 800 mg orally QD until disease progression, unacceptable toxicity or other reasons specified in the protocol

Other Name: Votrient

Drug: Sunitinib

For Arms 2C and 3C (TKI pazopanib or sunitinib):

Sunitinib 50 mg orally QD until disease progression, unacceptable toxicity or other reasons specified in the protocol

Other Name: Sutent




Primary Outcome Measures :
  1. ORR evaluation according to molecular groups (ccRCC1 to 4) and assigned treatment [ Time Frame: 54 months ]
    ORR evaluation according to molecular groups (ccRCC1 to 4) and assigned treatment (nivolumab monotherapy, nivolumab combined with ipilimumab, or TKI: sunitinib or pazopanib), based on Investigator assessments.


Secondary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: 54 months ]
    progression-free survival (PFS) in subjects with previously untreated mRCC according to molecular groups and assigned treatment, based on Investigator radiological assessments.

  2. Overall Survival [ Time Frame: 54 months ]
    To evaluate OS in subjects with previously untreated mRCC according to molecular groups and assigned treatment.

  3. Objective response rate at 22 weeks [ Time Frame: at 22 weeks ]
    To evaluate objective response rate at 22 weeks as a surrogate of other endpoints according to molecular groups and assigned treatment.

  4. Duration of treatment (DOT) [ Time Frame: 54 months ]
    To evaluate the duration of treatment (DOT) of nivolumab combined with ipilimumab or nivolumab alone or cabozantinib in subjects with previously untreated mRCC according to their molecular subgroup (1&4 vs 2&3).

  5. Duration of response (DOR) [ Time Frame: 54 months ]
    To evaluate the duration of response (DOR) of nivolumab combined with ipilimumab or nivolumab alone or cabozantinib in subjects with previously untreated mRCC according to their molecular subgroup (1&4 vs 2&3).

  6. Number of Participants With Treatment-Related Adverse Events [ Time Frame: 54 months ]
    To estimate the incidence of AEs associated with nivolumab combined with ipilimumab or nivolumab alone or cabozantinib in all treated subjects with previously untreated mRCC.

  7. Gene expression of immune population markers [ Time Frame: at baseline at progression (36 months maximum) ]
    To assess gene expression of immune population markers in the primary tumor as well as in the metastases before beginning treatment, and at progression if safely achievable.populations (CD3, CD8...) and regulatory markers (PD-1, LAG-3…) within the primary tumor, and metastases whenever possible, using frozen and FFPE tumor tissue.

  8. Gene expression levels obtained from FFPE [ Time Frame: at the end of the study (36 months) ]
    Gene expression levels obtained from FFPE tumor tissue (exploratory method) will be compared to those obtained with frozen tumor tissue (standard method).

  9. Functional status of peripheral blood lymphocytes (PBL) [ Time Frame: at baseline, at cycle 2 and at progression (36 months maximum) ]
    To assess the functional status of peripheral blood lymphocytes (PBL) by flow cytometry, before treatment initiation, during treatment, and at progression.

  10. Association between non-immune tissue and circulating biomarkers and outcomes [ Time Frame: 36 months maximum ]
    To explore the association between non-immune tissue and circulating biomarkers and outcomes (ORR, ORR at 22 weeks, OS and PFS).

  11. Mutation and methylation analysis of circulating tumor DNA [ Time Frame: 36 months maximum ]
    The initial rate of ctDNA and its evolution will be correlated to the clinical evolution of patients and progression-free survival.

  12. Genetic and epigenetic alterations [ Time Frame: 36 months maximum ]
    To identify genetic and epigenetic alterations associated with either response or resistance to immune checkpoint inhibitors and tyrosine kinase inhibitors.

  13. association between immune cells composing tumor microenvironment and response and/or resistance [ Time Frame: 36 months maximum ]
    To evaluate the association between immune cells composing tumor microenvironment and response and/or resistance to immune checkpoint inhibitors or tyrosine kinase inhibitors.

  14. additional genetic and epigenetic tumor alterations [ Time Frame: 36 months maximum ]
    To evaluate additional genetic and epigenetic tumor alterations at resistance/progression or after resection of residual mass.



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

Key Inclusion Criteria:

  • Histological confirmation of RCC with a clear-cell component. Patients with TFE3 or TFEB translocation proven by cytogenetic analysis or by fluorescence in situ hybridization (FISH) are eligible.
  • Metastatic (American Joint Committee on Cancer [AJCC] Stage IV) RCC
  • No prior systemic therapy for mRCC
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2
  • Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Frozen tumor samples (primary tumor and/or metastasis biopsies) must be available and received by the central laboratory (Cordelier Research Center) to determine molecular groups. (Note: fine needle aspiration [FNA] and bone metastases samples are not acceptable for submission).
  • Molecular group has to be determined prior to randomization.
  • Formalin-fixed, paraffin-embedded (FFPE) tumor tissue available for biomarker (gene expression and immunohistochemistry (IHC)) analysis.

Key Exclusion Criteria:

  • Any untreated CNS metastases. Patients with CNS metastases will be eligible if they are: asymptomatic, without significant oedema, not on corticosteroids, not eligible for radiation therapy/surgery or have already received radiation therapy.
  • Prior systemic treatment with vascular endothelial growth factor (VEGF) or VEGF receptor-targeted therapy (including, but not limited to, sunitinib, pazopanib, axitinib, tivozanib, and bevacizumab) except in an adjuvant setting with a free interval of more than 1 year.
  • Prior treatment with an anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
  • Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (>10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type 1 diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll.
  • Any condition requiring systemic treatment with corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  • Uncontrolled adrenal insufficiency.
  • Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or prolongation of the Fridericia corrected QT (QTcF) interval defined as >450 msec for males and >470 msec for females, where QTcF = QT / 3√RR.
  • Poorly controlled hypertension (defined as systolic blood pressure (SBP) of >150 mmHg or diastolic blood pressure (DBP) of >90 mmHg), despite antihypertensive therapy.
  • History of any of the following cardiovascular conditions within 12 months of enrollment: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association.
  • History of cerebrovascular accident including transient ischemic attack within the past 12 months.
  • History of deep vein thrombosis (DVT) unless adequately treated with low molecular weight heparin.
  • History of pulmonary embolism within the past 6 months unless stable, asymptomatic, and treated with low molecular weight heparin for at least 6 weeks.
  • Known history of COPD (of any stage).
  • Known history of uveitis or complaint of double vision.
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months.
  • Serious, non-healing wound or ulcer.
  • Evidence of active bleeding or bleeding susceptibility; or medically significant hemorrhage within prior 30 days.
  • Any requirement for anti-coagulation, except for low molecular weight heparin.
  • Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
  • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
  • Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
  • Known medical condition (e.g., a condition associated with diarrhea or acute diverticulitis) that, in the Investigator's opinion, would increase the risk associated with study participation or study drug administration, or interfere with the interpretation of safety results.
  • Known history of hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral motor neuropathy, peripheral sensory, neuropathy, and polyneuropathy.
  • Major surgery (e.g., nephrectomy) less than 35 days prior to the first dose of study drug.
  • Focal radiation therapy less than 14 days prior to the first dose of study drug.
  • Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of cabozantinib (e.g., malabsorptive disorder, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or small bowel resection).
  • Any of the following laboratory test findings:

    1. WBC <2,000/mm3
    2. Hemoglobin ≤9.0 g/dL
    3. Neutrophils <1,500/mm3
    4. Platelets <100,000/mm3
    5. AST or ALT >3 x ULN (>5 x ULN if liver metastases are present)
    6. Lipase and amylase > 1.5 ULN
    7. Total Bilirubin >1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin <3.0 mg/dL)
    8. Serum creatinine >1.5 x ULN or creatinine clearance <40 mL/min (measured or calculated by Cockroft-Gault formula)
    9. Proteinuria: patients with ≥2+ protein on urine dipstick at baseline must undergo a 24-hour urine collection for protein then if > 1.0 g of protein patient will not be included.

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): NCT02960906


Locations
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France
Hôpital Saint André, CHU de Bordeaux
Bordeaux, France, 33075
Centre Francois Baclesse
Caen, France, 14000
CHU Henri-Mondor
Creteil, France, 94000
Centre OSCAR LAMBRET LILLE
Lille, France, 59000
Institut Paoli Calmettes (IPC)
Marseille, France, 13009
Centre Antoine Lacassagne
Nice, France, 06100
Institut de Cancérologie du Gard - CHU Caremeau
Nîmes, France, 30029
Institut Mutualiste Montsouris
Paris, France, 75014
Hôpital Européen Georges Pompidou
Paris, France, 75015
Hôpital Cochin
Paris, France, 75679
Centre Hospitalier Lyon Sud - Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL)
Pierre Bénite, France, 69310
Centre Eugene Marquis
Rennes, France, 35042
Hôpitaux universitaires de Strasbourg
Strasbourg, France, 67000
Hopital Foch
Suresnes, France, 92151
Institut Claudius Regaud
Toulouse, France, 31059
CHU Bretonneau
Tours, France, 37000
Sponsors and Collaborators
Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie
Investigators
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Principal Investigator: Yann-Alexandre VANO, MD Hôpital Européen Georges Pompidou; Oncology department of Pr Stéphane OUDARD
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie
ClinicalTrials.gov Identifier: NCT02960906    
Other Study ID Numbers: BIONIKK
First Posted: November 10, 2016    Key Record Dates
Last Update Posted: April 26, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma, Renal Cell
Kidney Neoplasms
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Nivolumab
Ipilimumab
Sunitinib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors