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Radio-immunotherapy (CDX-301, Radiotherapy, CDX-1140 and Poly-ICLC) for the Treatment of Unresectable or Metastatic Breast Cancer Patients

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ClinicalTrials.gov Identifier: NCT04616248
Recruitment Status : Not yet recruiting
First Posted : November 4, 2020
Last Update Posted : April 21, 2021
Sponsor:
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Brief Summary:
This phase I trial evaluates the side effects of radio-immunotherapy (CDX-301, radiotherapy, CDX-1140 and Poly-ICLC) in treating patients with breast cancer that cannot be removed by surgery (unresectable) and has spread to other places in the body (metastatic). CDX-301 may induce cross-presenting dendritic cells, master regulators in the immune system. Radiation therapy uses high energy to kill tumor cells and release antigens that may be picked up, processed and presented by cross-presenting dendritic cells. CDX-1140 and Poly-ICLC may activate tumor antigen-loaded,cross-presenting dendritic cells, and generate tumor-specific T lymphocytes, a type of immune cells, that can search out and attack cancers. Giving immune modulators and radiation therapy may stimulate tumor cell death and activate the immune system.

Condition or disease Intervention/treatment Phase
Anatomic Stage IV Breast Cancer AJCC v8 Metastatic Breast Carcinoma Prognostic Stage IV Breast Cancer AJCC v8 Unresectable Breast Carcinoma Biological: Anti-CD40 Agonist Monoclonal Antibody CDX-1140 Drug: Poly ICLC Radiation: Radiation Therapy Biological: Recombinant Flt3 Ligand Phase 1

Detailed Description:

PRIMARY OBJECTIVE:

I. To evaluate the safety profile of in situ immunomodulation with recombinant Flt3 ligand (CDX-301), radiotherapy, agonistic anti-CD40 monoclonal antibody CDX-1140, and Poly-ICLC in unresectable and metastatic breast cancer patients with injectable palpable disease.

SECONDARY OBJECTIVE:

I. To evaluate the immune signatures in the tumor microenvironment before and after in situ immunomodulation with CDX-301, radiotherapy, CDX-1140, and Poly-ICLC.

EXPLORATORY OBJECTIVES:

I. To record the overall response rate (ORR) (complete response [CR] and partial response [PR]) of distant uninjected metastatic lesions in metastatic breast cancer patients with injectable palpable disease treated with in situ immunomodulation with CDX-301, radiotherapy, CDX-1140, and Poly-ICLC by immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) response assessment, and compare intratumoral alone versus (vs.) intratumoral + intravenous administration of CDX-1140.

II. To record the overall survival (OS) and progression free survival (PFS) in unresectable and metastatic breast cancer patients with injectable palpable disease treated with in situ immunomodulation with CDX-301, radiotherapy, CDX-1140, and Poly-ICLC, and compare intratumoral alone vs. intratumoral + intravenous administration of CDX-1140.

III. Examine changes in the levels of T-cell subsets/myeloid derived suppressor cells (MDSC)/cytokines in peripheral blood (PB) of unresectable and metastatic breast cancer patients with injectable palpable disease treated with in situ immunomodulation with CDX-301, radiotherapy, CDX-1140, and Poly-ICLC.

OUTLINE:Cohort A will evaluate safety of intratumoral administration of CDX-1140 in combination with CDX-301, radiotherapy and Poly-ICLC. Once cohort A is finished, patients will be enrolled to cohort B to evaluate safety of intratumoral + intravenous administration of CDX-1140 in combination with CDX-301, radiotherapy and Poly-ICLC.

COHORT A: Patients receive recombinant Flt3 ligand intratumorally (IT) on days 1-5 and agonistic anti-CD40 monoclonal antibody CDX-1140 IT with Poly-ICLC IT on day 9 or 10. Patients also undergo radiation therapy on day 8 or 9. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

COHORT B: Patients receive recombinant Flt3 ligand IT on days 1-5 and agonistic anti-CD40 monoclonal antibody CDX-1140 IT and intravenously (IV) over 90 minutes with Poly-ICLC IT on day 9 or 10. Patients also undergo radiation therapy on day 8 or 9. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 6 months for 2 years.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of In Situ Immunomodulation With CDX-301, Radiotherapy, CDX-1140, and Poly-ICLC in Unresectable and Metastatic Breast Cancer Patients With Injectable Palpable Disease
Estimated Study Start Date : May 15, 2021
Estimated Primary Completion Date : May 15, 2022
Estimated Study Completion Date : May 15, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Cohort A (immunomodulators, radiation therapy)
Patients receive recombinant Flt3 ligand IT on days 1-5 and undergo radiation therapy on day 8 or 9. Patients also receive agonistic anti-CD40 monoclonal antibody CDX-1140 IT and Poly-ICLC IT on day 9 or 10. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.
Biological: Anti-CD40 Agonist Monoclonal Antibody CDX-1140
Given IT
Other Names:
  • Agonist CD40 Antibody CDX-1140
  • Anti-CD40 Agonistic Monoclonal Antibody CDX-1140
  • CDX 1140
  • CDX-1140

Drug: Poly ICLC
Given IT
Other Names:
  • Hiltonol
  • Poly I:Poly C with Poly-L-Lysine Stabilizer
  • poly-ICLC
  • PolyI:PolyC with Poly-L-Lysine Stabilizer
  • Polyinosinic-Polycytidylic Acid Stabilized with Polylysine and Carboxymethylcellulose
  • Polyriboinosinic-Polyribocytidylic Acid-Polylysine Carboxymethylcellulose
  • Stabilized Polyriboinosinic/Polyribocytidylic Acid

Radiation: Radiation Therapy
Undergo radiation therapy
Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation

Biological: Recombinant Flt3 Ligand
Given IT
Other Names:
  • CDX-301
  • FLT 3 Ligand
  • FLT3 Ligand
  • Flt3-Ligand
  • Flt3L
  • Mobist
  • Mobista
  • rhuFlt3L

Experimental: Cohort B (immunomodulators, radiation therapy)
Patients receive recombinant Flt3 ligand IT on days 1-5 and undergo radiation therapy on day 8 or 9. Patients also receive agonistic anti-CD40 monoclonal antibody IT and IV over 90 minutes and Poly-ICLC IT on day 9 or 10. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.
Biological: Anti-CD40 Agonist Monoclonal Antibody CDX-1140
Given IT
Other Names:
  • Agonist CD40 Antibody CDX-1140
  • Anti-CD40 Agonistic Monoclonal Antibody CDX-1140
  • CDX 1140
  • CDX-1140

Drug: Poly ICLC
Given IT
Other Names:
  • Hiltonol
  • Poly I:Poly C with Poly-L-Lysine Stabilizer
  • poly-ICLC
  • PolyI:PolyC with Poly-L-Lysine Stabilizer
  • Polyinosinic-Polycytidylic Acid Stabilized with Polylysine and Carboxymethylcellulose
  • Polyriboinosinic-Polyribocytidylic Acid-Polylysine Carboxymethylcellulose
  • Stabilized Polyriboinosinic/Polyribocytidylic Acid

Radiation: Radiation Therapy
Undergo radiation therapy
Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation

Biological: Recombinant Flt3 Ligand
Given IT
Other Names:
  • CDX-301
  • FLT 3 Ligand
  • FLT3 Ligand
  • Flt3-Ligand
  • Flt3L
  • Mobist
  • Mobista
  • rhuFlt3L




Primary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 30 days ]
  2. Maximum tolerated dose or maximum administered dose [ Time Frame: Up to 30 days ]
    The dose limiting toxicity rate will be estimated by cohort and dose-level (if appropriate) using 90% confidence intervals obtained by Jeffrey's prior method.


Secondary Outcome Measures :
  1. Changes in Immune signatures in the tumor microenvironment [ Time Frame: Baseline up to 2 years ]
    Will examine changes in the immune biomarkers levels from baseline to end of treatment

  2. Changes in the levels of infiltrating CD4+ and CD8+ T cells [ Time Frame: Baseline up to 2 years ]
    Will examine changes in the levels of infiltrating CD4+ and CD8+ T cells and their proteomic, genomic and transcriptomic signatures in the tumor microenvironment. The immune biomarker levels are treated as continuous variables and will be summarized in the overall sample and within treatment-arm by time-point using the mean and standard error, and graphically using dot-plots.

  3. Changes in the levels of infiltrating myeloid cell subsets [ Time Frame: Baseline up to 2 years ]
    Will examine changes in the levels of infiltrating myeloid cell subsets including dendritic cells (DCs), macrophages, and monocytes, and their proteomic, genomic and transcriptomic signatures in the tumor microenvironment. The immune biomarker levels are treated as continuous variables and will be summarized in the overall sample and within treatment-arm by time-point using the mean and standard error, and graphically using dot-plots.

  4. Changes in the levels of PD-L1 expression [ Time Frame: Baseline up to 2 years ]
    Will examine changes in the levels of PD-L1 expression within both neoplastic and nonneoplastic stromal elements of the tumor microenvironment. The immune biomarker levels are treated as continuous variables and will be summarized in the overall sample and within treatment-arm by time-point using the mean and standard error, and graphically using dot-plots.


Other Outcome Measures:
  1. Overall response rate (ORR) [ Time Frame: Up to 2 years ]
    ORR of distant uninjected metastatic lesions is defined as partial or complete response within 6 months of initiating combination therapy. Overall response will be summarized overall and by cohort using frequencies and relative frequencies, where the overall response rate will be estimated using a 90% confidence interval obtained by Jeffrey's prior method.

  2. Overall survival [ Time Frame: From treatment initiation until death due to any cause (event) or last follow-up, assessed up to 2 years ]
    Will be summarized in the overall sample and by cohort using standard Kaplan-Meier methods; where estimates of the median will be obtained with 90% confidence intervals.

  3. Progression free survival [ Time Frame: From treatment initiation until disease progression, death due to disease (events), or last follow-up, assessed at 1 year ]
    Will be summarized in the overall sample and by cohort using standard Kaplan-Meier methods; where estimates of the median will be obtained with 90% confidence intervals.

  4. Changes in the levels of peripheral blood (PB) biomarkers [ Time Frame: Baseline up to 2 years ]
    Will examine changes in the levels of PB biomarkers such as T-cell subsets/myeloid derived suppressor cells (MDSC)/cytokines in metastatic breast cancer patients treated with in situ immunomodulation with CDX-301, radiotherapy, CDX-1140, and poly-ICLC.



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:

  • Have clinically or pathologically confirmed diagnosis of unresectable and metastatic breast cancer with no curative treatment options
  • Have been informed of other treatment options
  • Patient must have lesion that can be biopsied and is willing to undergo the procedure as part of the protocol
  • Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 1
  • Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • For patients with history of radiotherapy to the same side of chest wall/breast, he/she will be eligible only if doses under 70 Gy total to the chest wall, if delivered more than 6 months prior to planned re-treatment
  • Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, and documented available breast tumor for injections: the longest axis of the tumor is at least 1 cm
  • Have measurable distant disease per RECIST 1.1 criteria present
  • Any line of therapy allowed, radiologically or clinically confirmed progression on prior therapy
  • No cancer-directed therapy for at least 3 weeks prior to study treatment (bone-directed therapies are allowed)
  • Platelets >= 100,000/uL
  • Hemoglobin >= 9.0 g/dL
  • Absolute neutrophil count (ANC) >= 1500/uL
  • Total bilirubin =< 1.5 X institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional ULN
  • Creatinine =< 1.5 X ULN OR creatinine clearance >= 50 mL/min per Cockcroft-Gault equation for patients with creatinine levels greater than ULN
  • Participant or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure
  • Patients must agree to injections of CDX-301, CDX-1140, and poly-ICLC
  • Patients must agree to radiation to the breast tumor
  • Patients must agree to appropriate clinical monitoring to receive the study regimens
  • Patients must agree to photos of tumors and use of the photos for publication
  • Patients should have an administration site for all injections that is free of potentially complicating dermatologic conditions such as rashes and should not be located in an area where the integrity of the draining lymph node bed is potentially compromised (i.e., an extremity where a nodal resection was previously performed)

Exclusion Criteria:

  • Patients currently treated with systemic immunosuppressive agents, including steroids, are ineligible until 3 weeks after removal from immunosuppressive treatment. (inhaled steroids are allowed)
  • Patients with active or history of autoimmune disease or history of transplantation
  • Patients with active or prior history of non-infectious pneumonitis
  • Patients with prior history of acute myeloid leukemia (AML) or known FLT3 aberrations
  • Pregnant or nursing female participants
  • Unwilling or unable to follow protocol requirements
  • Patients with known serious mood disorders. (Major depression diagnosis is an exclusion: Other stable mood disorders on stable therapy for > 6 months or not requiring therapy may be allowed after consultation with principal investigator [PI])
  • Cardiac risk factors including:

    • Patients experiencing cardiac event(s) (acute coronary syndrome, myocardial infarction, or ischemia) within 3 months of signing consent
    • Patients with a New York Heart Association classification of III or IV
  • Patients with inflammatory breast cancer
  • Patients with uncontrolled diseases other than cancer may be excluded if after consultation with PI and research team it is decided it might affect the treatment efficacy or toxicity
  • Evidence of current drug or alcohol abuse or psychiatric impairment, which in the investigator's opinion will prevent completion of the protocol therapy or follow-up. Specific testing is not required, however may be done as clinically indicated
  • Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug
  • Participants with symptomatic known brain metastases < 4 weeks from radiation treatment should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
  • Other invasive cancers diagnosed < 3 years back that required systemic treatment. If diagnosed with other invasive cancer >= 3 years, should have complete recovery from all systemic toxicity except neuropathy and alopecia
  • Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine
  • Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
  • Chemotherapy, radiation therapy, or immunotherapy within 3 weeks prior to first dosing of study agent. Concomitant hormonal therapies are allowed
  • Current use of anticoagulants (warfarin, heparin, direct thrombin inhibitors) at therapeutic levels

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): NCT04616248


Locations
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United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Contact: Fumito Ito    716-845-5601    Fumito.Ito@roswellpark.org   
Principal Investigator: Fumito Ito         
Sponsors and Collaborators
Roswell Park Cancer Institute
Investigators
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Principal Investigator: Fumito Ito Roswell Park Cancer Institute
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Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT04616248    
Other Study ID Numbers: I 569819
NCI-2020-07826 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
I 569819 ( Other Identifier: Roswell Park Cancer Institute )
First Posted: November 4, 2020    Key Record Dates
Last Update Posted: April 21, 2021
Last Verified: April 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Carcinoma
Breast Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Poly I-C
Antineoplastic Agents, Immunological
Carboxymethylcellulose Sodium
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Poly ICLC
Flt3 ligand protein
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Interferon Inducers
Laxatives
Gastrointestinal Agents
Antiviral Agents
Anti-Infective Agents
Adjuvants, Immunologic
Radiation-Protective Agents
Protective Agents