CLINICAL TRIAL / NCT05029999
CD40 Agonist, Flt3 Ligand, and Chemotherapy in Triple Negative Breast Cancer
- Interventional
- Recruiting
- NCT05029999
Contact Information
Phase 1 Pilot Study With Dose Expansion of Chemotherapy in Combination With CD40 Agonist and Flt3 Ligand in Metastatic Triple Negative Breast Cancer
This research study is being done to find out if the immunotherapy drugs called CDX-301 and CDX-1140 in combination with the standard chemotherapy treatment pegylated liposomal doxorubicin (PLD, Doxil) are safe and effective at controlling the cancer in patients with metastatic triple negative breast cancer, and to determine a safe dose and treatment schedule of the three drugs. This research study will also test how these treatments improve your body's immune response against the cancer.
The immunotherapy drugs CDX-301 and CDX-1140 in combination with the standard chemotherapy
treatment PLD work by kickstarting the immune response against cancer cells. CDX-301
increases the antigen presenting immune cells needed to kickstart the immune response,
CDX-1140 activates these cells, and chemotherapy helps release antigens from the cancer cells
to train these antigen presenting immune cells to recognize the cancer for the immune system
to attack it.
Metastatic or unresectable triple negative breast cancer patients will receive this triplet
combination that has been shown in preclinical studies to be more effective than the
individual treatments or doublet combinations. To understand how the immunotherapies are
working, some patients will receive the immunotherapy or chemotherapy only for one cycle
prior to receiving the full triplet combination therapy. Ultimately, all patients will
receive the triplet combination to study safety and how effective this treatment is at
controlling triple negative breast cancer and improving survival outcomes.
Gender
All
Age Group
18 Years to 99 Years
Accepting Healthy Volunteers
No
Inclusion Criteria:
- Unresectable Stage III or Stage IV Triple Negative Breast cancer
- Age 18 years or older
- Performance status ECOG 0-2
- Life expectancy ≥ 12 weeks
- Documented progressive disease, based on radiographic, clinical or pathologic
assessment, during or subsequent to last anticancer therapy. Patients who need to
change systemic therapy for other indications such as toxicity that are otherwise
eligible for this study may enroll with approval of the lead principal investigator.
- For initial safety cohort, subject is in second to third line setting of treatment for
metastatic or unresectable disease, and have received 1 to 2 prior regimens for
metastatic or unresectable disease. For dose expansion, subject is in first to third
line setting of treatment for metastatic or unresectable disease, and have received 0
to 2 prior regimens for metastatic or unresectable disease.
- Among any patient enrolled in the first line treatment setting, subjects must be PD-L1
negative by 22C3 assay and not be eligible for FDA approved standard of care
chemotherapy and anti-PD-1/PD-L1 combination therapy as alternative to this clinical
trial.
- Screening laboratory values must meet the following criteria:
- Neutrophils ≥ 1500/uL
- Platelets ≥ 100 x10(9)/L
- Hemoglobin ≥ 8 g/dL Patients may receive erythrocyte transfusions to achieve this
hemoglobin level at the discretion of the investigator. Initial treatment must
not begin earlier than the day after the erythrocyte transfusion.
- Creatinine ≤ 2 mg/dL
- Creatinine clearance >30 mL/minute
- AST ≤ 2.5 X ULN without, and ≤ 5 x ULN with hepatic metastasis
- ALT ≤ 2.5 X ULN without, and ≤ 5 x ULN with hepatic metastasis
- Total Bilirubin ≤ 1.5 X ULN (except patients with Gilbert's syndrome or liver
involvement, who must have a total bilirubin ≤ 2 X ULN)
- Alkaline phosphatase ≤ 2.5 X ULN without, and ≤ 5 x ULN with hepatic metastasis
- All men as well as women of child bearing potential enrolled in this trial must agree
to use effective contraception during the course of the trial and for at least 6
months after discontinuing study treatment. Patients and/or partners who are
surgically sterile or postmenopausal are exempt from this requirement.
- A female of child-bearing potential is any woman (regardless of sexual
orientation, marital status, having undergone a tubal ligation, or remaining
celibate by choice) who meets the following criteria: ( 1) has not undergone a
hysterectomy or bilateral oophorectomy OR (2) has not been naturally
postmenopausal for at least 12 consecutive months (i.e., has had menses at any
time in the preceding 12 consecutive months).
- Provision of consent for pre-treatment and on-treatment biopsies. Biopsy sites must be
soft tissue tumor lesions or accessible visceral diseases that can be biopsied with
acceptable clinical risk (as judged by the investigator); are large enough to allow
for the collection of tumor tissue for proposed correlative studies (e.g., anticipated
goal of 6-8 cores preferred when feasible using a ≥ 18 gauge needle with an expected
core sample length of 5 mm); and have not been irradiated prior to entry. This does
not include bone lesions. This may exclude many lung lesions and small lesions.
- Measurable disease allowing for serial assessment of at least one target lesion(s) by
RECIST 1.1 criteria [100]. Target lesions selected for tumor measurements should be
those where additional (e.g., palliative) treatments are not indicated or anticipated.
- All residual toxicity related to prior anticancer therapies (excluding alopecia, grade
2 fatigue, vitiligo, endocrinopathies on stable replacement therapy, grade 2
neuropathy from taxanes or platinum and grade 2 hearing loss from platinum) must
resolve to grade 1 severity or less (or returned to baseline) prior to receipt of
study treatment.
- Read, understood, and provided written informed consent, and if applicable, Health
Insurance Portability and Accountability Act (HIPAA) authorization, after the nature
of the study has been fully explained, and must be willing to comply with all study
requirements and procedures.
Exclusion Criteria:
- Among any patients enrolled in the first line treatment setting, tumors should not be
PD-L1+ by 22C3 assays or eligible for FDA approved standard of care chemotherapy and
anti-PD-1/PD-L1 combination therapy as alternative to this clinical trial.
- History of severe hypersensitivity reactions to mAbs.
- Prior treatment with any anti-CD40 antibody or rhuFlt3L product.
- Treatment with anthracycline in the metastatic setting.
- Prior progression while on anthracycline based therapy or within 6 months of
completing (neo)adjuvant anthracycline.
- Prior history of acute myeloid leukemia (AML), or tumor with known Flt3
mutation/amplification
- Receipt of any antibody targeting T cell check point or co-stimulation pathways within
4 weeks, use of any other monoclonal based therapies within 4 weeks, and all other
immunotherapy (tumor vaccine, cytokine, or growth factor given to control the cancer)
within 2 weeks prior to the planned start of study treatment.
- Prior T-cell or other cell-based therapies within 12 weeks (or 2 weeks if patient
experienced disease progression on the prior treatment)
- Systemic radiation therapy within 4 weeks, prior focal radiotherapy within 2 weeks, or
radiopharmaceuticals (strontium, samarium) within 8 weeks prior to the first dose of
study treatment.
- Chemotherapy within 21 days or at least 5 half-lives (whichever is shorter) prior to
the planned start of study treatment.
- Any kinase inhibitors within 2 weeks prior to the first dose of study treatment.
- Major surgery within 4 weeks prior to the first dose of study treatment. Surgery
requiring local/epidural anesthesia must be completed at least 72 hours before study
drug administration and patients should be recovered.
- Use of other investigational drugs within 4 weeks or 5 half-lives (whichever is
longer) prior to study treatment administration.
- Use of immunosuppressive medications within 4 weeks or systemic corticosteroids within
2 weeks prior to first dose of study treatment. Topical, inhaled or intranasal
corticosteroids (with minimal systemic absorption) may be continued if the patient is
on a stable dose. Non-absorbed intraarticular corticosteroid and replacement steroids
(≤ 10 mg/day prednisone or equivalent) will be permitted.
- Other prior malignancy, except for adequately treated basal or squamous cell skin
cancer or in situ cancers; or any other cancer from which the patient has been
disease-free for at least 3 years.
- Active, untreated central nervous system metastases.
- Patients with known treated brain metastases should be neurologically stable for 4
weeks post-treatment and prior to study enrollment. Continued use of steroids and/or
anticonvulsants (in the absence of any suspicion of progressive brain metastases) is
acceptable if ≤ equivalent of prednisone 10 mg daily. Brain MRI required on screening
to document lack of progression.
- Women who are pregnant or nursing. All female patients with reproductive potential
must have a negative pregnancy test prior to starting treatment.
- Active autoimmune disease or history of autoimmune disease or syndrome that required
systemic steroids or immunosuppressive medications within the preceding 6 months,
except for patients with vitiligo, endocrinopathies, or type 1 diabetes, Patients with
mild asthma who require intermittent use of bronchodilators (such as albuterol) who
have not been hospitalized for asthma in the preceding 6 months will not be excluded
from this study.
- Significant cardiovascular disease including unstable angina pectoris, uncontrolled
hypertension or arrhythmia, congestive heart failure (New York Heart Association Class
III or IV or EF<50%) related to primary cardiac disease, uncontrolled ischemic or
severe valvular heart disease or any of the following within 6 months prior to the
first dose of study treatment: myocardial infarction, severe/unstable angina, coronary
artery bypass graft, congestive heart failure, cerebrovascular accident, transient
ischemic attack.
- Prior anthracycline therapy with a cumulative doxorubicin-equivalent dose greater than
240 mg/m2.
- Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. The
COVID-19 vaccines available in the United States are not live vaccines and are allowed
if the final vaccine dose (of a regimen that requires more than 1 dose) is received at
least 1 week prior to study enrollment.
- History of (non-infectious) pneumonitis or has current pneumonitis. This includes
asymptomatic infiltrates on screening chest CT scan that are felt by the investigator
to potentially be an inflammatory process (i.e. grade 1 pneumonitis).
- Active infection requiring systemic therapy, known HIV infection, or positive test for
hepatitis B surface antigen or hepatitis C (antibody screen and if positive confirmed
by RNA analysis). If positive results are not indicative of a true active or chronic
infection, the patient can be enrolled after discussion with and agreement by the
Investigator.
- Any other acute or chronic medical or psychiatric condition or laboratory abnormality
that could increase the risk associated with trial participation or trial drug
administration or could interfere with the interpretation of trial results and, in the
judgment of the investigator, would make the patient inappropriate for entry into the
trial.
- Evidence of acute or chronic infection on screening chest radiography.