Personalized Neoantigen Cancer Vaccine with and without Low-Dose Cyclophosphamide or Pembrolizumab for the Treatment IGHV Unmutated Chronic Lymphocytic Leukemia
This early phase I trial studies the effects of personalized neoantigen cancer vaccine with and without low-dose cyclophosphamide or pembrolizumab in treating patients with IGVH unmutated chronic lymphocytic leukemia. Personalized neoantigen cancer vaccine will consist of up to 20 of these peptides as well as a drug called Poly-ICLC. Poly-ICLC binds proteins on the surface of certain immune cells to make it appear as if a virus is present. When the cells detect the vaccine, they think it is a virus and turn on the immune system. Chemotherapy drugs, such as low-dose cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This study examines the feasibility and safety in giving personalized neoantigen cancer vaccine with and without low-dose cyclophosphamide or pembrolizumab to patients with chronic lymphocytic leukemia.
Inclusion Criteria
- SCREENING REGISTRATION
- Diagnosis of CLL as per iw-CLL 2018 criteria
- Patient’s CLL must have an unmutated immunoglobulin heavy chain variable (IGHV) region gene, defined as < 2% mutated compared to germline
- Patient must have had no history of CLL-directed therapy due to meeting iw-CLL 2018 criteria; no present indication for treatment by iwCLL 2018 criteria; and in the opinion of the treating investigator be anticipated not to require CLL-directed treatment within the next 6 months
- Patient must have measurable disease (absolute lymphocyte count [ALC] > 10,000/uL or total white blood cell count >= 20,000/uL of peripheral blood)
- Patient must have had at least two other ALC measured since diagnosis of CLL that are at least 2 weeks apart and at least 2 months prior to the one used for initial registration
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- Total bilirubin within normal institutional limits
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
- Absolute neutrophil count >= 1000 cells/uL
- The effects of NeoVax and poly-ICLC on the developing human fetus are unknown. For this reason, women of childbearing potential (WOCBP) must have a negative pregnancy test (minimum sensitivity 25 IU/L or equivalent of HCG) before entry onto the trial and within 7 days prior to start of study medication. It is the investigators’ responsibility to repeat the pregnancy test should start of treatment be delayed
- Female patients enrolled in the study, who are not free from menses for > 2 years, post hysterectomy / oophorectomy, or surgically sterilized, must be willing to use either 2 adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy or to abstain from sexual activity throughout the study, starting with visit 1 through 4 weeks after the last dose of study therapy. Approved contraceptive methods include for example; intra uterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, or female condom with spermicide. Spermicides alone are not an acceptable method of contraception
- Patient is agreeable to allow tumor (from peripheral blood) and normal tissue (from saliva) samples to be submitted for complete exome and transcriptome sequencing
- Ability to understand and the willingness to sign a written informed consent document
- ADDITIONAL CRITERIA FOR TREATMENT REGISTRATION
- At least 7 immunizing peptides can be designed
- Continue to meet inclusion and exclusion criteria for Screening Registration
Exclusion Criteria
- Prior therapy for CLL that met iw-CLL treatment criteria, including chemotherapy, targeted therapies (e.g. that antagonize B cell receptor signaling), or immunotherapy (including but not limited to monoclonal antibodies); or radiotherapy or hormonal therapy within the last 2 years of screening registration
- Participants who are receiving any other investigational agents
- Previous bone marrow or stem cell transplant
- Concomitant therapy with immunosuppressive or immunomodulatory agents; chronic use of systemic corticosteroids. Previous history of corticosteroid use is acceptable. Use of corticosteroids after initial registration is acceptable if tapered at least one week before NeoVax administration
- Use of a non-oncology vaccine therapy for prevention of infectious diseases within 2 weeks of any NeoVax administration. Vaccination against SARS-CoV-2 are allowed
- History of severe allergic reactions attributed to any vaccine therapy for the prevention of infectious diseases
- Participants who have never received the tetanus vaccine
- Active, known, or suspected autoimmune disease or immunosuppressive conditions with the exception of vitiligo, type 1 diabetes, residual autoimmune-related hypothyroidism requiring hormone replacement, or psoriasis not requiring systemic treatment
- Uncontrolled autoimmune cytopenia
- No lymph node > 5 cm by computed tomography (CT) scan (measured as long axis)
- Del(17p) by fluorescence in situ hybridization in >= 10% of CLL cells analyzed
- Any documented transformation of CLL (i.e. Richter’s syndrome)
- Lymphocyte doubling time (LDT) < 6 months in patients with white blood cell (WBC) > 30,000/uL. Factors contributing to lymphocytosis other than CLL (e.g. infections) should be excluded when calculating the LDT
- Serum immunoglobulin level < 400 mg/dL or currently requiring chronic intravenous immunoglobulin G (IVIG)
- Known chronic infections with human immunodeficiency virus (HIV), hepatitis B or C
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia
- Any underlying medical condition, psychiatric condition or social situation that in the opinion of the investigator would compromise study administration as per protocol or compromise the assessment of adverse events (AEs)
- Pregnant women are excluded from this study because personalized neoantigen peptides and poly-ICLC are agents with unknown risks to the developing fetus. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with personalized neoantigen peptides and poly-ICLC, nursing women are excluded from this study
- Individuals with history of an invasive malignancy are ineligible except for the following circumstances: * Individuals with a history of invasive malignancy are eligible if they have been disease –free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; * Individuals with the following cancers are eligible if diagnosed and treated: carcinoma in situ of the breast, oral cavity or cervix and basal cell or squamous cell carcinoma of the skin; * Individuals with prostate cancer managed with active surveillance that is not expected to limit their survival to < 10 years
- Participants with known central nervous system (CNS) involvement 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
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to poly-ICLC
- HIV-positive participants on combination antiretroviral therapy are ineligible because assessment of immunologic endpoints may be confounded by HIV-induced alterations in patient immune status and function. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03219450.
PRIMARY OBJECTIVE:
I. To evaluate the feasibility of administering NeoVax + T helper peptide, NeoVax + T helper peptide + LD-CTX, or NeoVax + T helper peptide + pembrolizumab based on its safety, tolerability and practicability in patients with treatment naive, immunoglobulin heavy chain variable (IGHV)-unmutated chronic lymphocytic leukemia (CLL) on observation who are not anticipated by the treating physician to require treatment for at least 6 months.
SECONDARY OBJECTIVES:
I. To assess the induction of neoantigen-specific cellular immune responses following administration of NeoVax in Cohorts A, B, and C.
II. The proportion of patients in each cohort who show vaccine-induced neoantigen-specific CD8+ T cell responses
III. To estimate tumor overall response rate (ORR), complete and partial response rates (including response rates for absolute lymphocyte count and lymph nodes), progression free survival by 2018 International Workshop on Chronic Lymphocytic Leukemia (IW-CLL) criteria, and time to first therapy after administration of NeoVax in Cohorts A, B, and C.
OUTLINE: Patients are assigned to 1 of 3 cohorts.
COHORT A: Patients receive personalized neoantigen vaccine and poly ICLC subcutaneously (SC) on days 1, 4, 8, 15, 22, 78, and 134 in the absence of disease progression or unacceptable toxicity. Within 7-14 days after administered of day 78 vaccine, patients receive personalized neoantigen vaccine SC in the absence of disease progression or unacceptable toxicity.
COHORT B: Patients receive personalized neoantigen vaccine and poly ICLC SC on days 1, 4, 8, 15, 22, 78, and 134 in the absence of disease progression or unacceptable toxicity. Within 7-14 days after administered of day 78 vaccine, patients receive personalized neoantigen vaccine SC in the absence of disease progression or unacceptable toxicity. Patients also receive low-dose cyclophosphamide orally (PO) twice daily (BID) every other week over 8 weeks in the absence of disease progression or unacceptable toxicity.
COHORT C: Patients receive personalized neoantigen vaccine and poly ICLC SC on days 1, 4, 8, 15, 22, 78, and 134 in the absence of disease progression or unacceptable toxicity. Within 7-14 days after administered of day 78 vaccine, patients receive personalized neoantigen vaccine SC in the absence of disease progression or unacceptable toxicity. Patients also receive low-dose cyclophosphamide PO BID every other week over 8 weeks in the absence of disease progression or unacceptable toxicity. Beginning week 12, patients receive pembrolizumab intravenously (IV) over 30 minutes every 3 weeks for up to 17 cycles in the absence of disease progression or unacceptable toxicity.
Patients undergo computed tomography (CT), bone marrow biopsy and aspirate and blood and saliva sample collection throughout the study.
After completion of study treatment, patients are followed up every 2-3 months until initiation of a new therapy for progressive disease or withdrawal of consent, whichever occurs first, for a maximum of 2 years. After two years, patients are followed via medical record review until death for survival.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorInhye E Ahn
- Primary ID17-105
- Secondary IDsNCI-2021-03482
- ClinicalTrials.gov IDNCT03219450