This research study evaluates the feasibility and tolerability of an investigational
intervention and also tries to define the appropriate dose of the investigational
intervention to use for further studies. "Investigational" means that the intervention is
being studied and that research doctors are trying to find more about it. It also means that
the FDA (US Food and Drug Administration) has not approved the Personalized Neoantigen Cancer
Vaccine for any use in patients, including people with CLL.
This is the first time NeoVax vaccine will be given in combination with cyclophosphamide in
The purpose of this study is to determine if it is possible to make and safely administer a
vaccine against CLL. The investigators plan to analyze the specific genetic characteristics
(mutations) of the participant's own CLL and use that information to produce proteins that
may help the immune system recognize and fight CLL cells.
This vaccine is also being tested in clinical trials in patients with advanced melanoma (a
type of skin cancer) or glioblastoma (a type of brain cancer). The current study will examine
the ability of the vaccine to stimulate the immune system when given at several different
timepoints, and will examine the participant blood cells for signs that the CLL has changed
CLL cells will be obtained from bone marrow biopsy and blood draws. The genetic material
contained in the CLL cells will be examined for the presence of tumor-specific mutations.
This information will be used to prepare small protein fragments, which are called
"peptides." The vaccine will consist of up to 20 of these peptides as well as a drug called
Poly-ICLC. A peptide from the tetanus vaccine will also be included to boost the immune
response. Half of the patients, enrolled in the second half of this trial, will also receive
low doses of a chemotherapy drug called cyclophosphamide.
Poly-ICLC (also called Hiltonol) is an experimental "viral mimic" and an activator of
immunity. 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. Poly-ICLC will be mixed with NeoAntigen peptides and administered
as an injection given underneath the skin. Poly-ICLC is an investigational drug, meaning the
FDA has not approved it as a treatment for any disease.
Cyclophosphamide (also called Cytoxan) is a chemotherapy drug used to treat many cancers,
including CLL. At the much lower dose used in this study, it is an investigational drug to
help the immune cells to be better at attacking cancer cells.
- Diagnosis of CLL as per IW-CLL 2008 criteria1
- 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 2008
criteria; no present indication for treatment by iwCLL 2008 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 > 10K/uL or total
white blood cell count ≥ 20K/uL of peripheral blood).
- Patient must have had at least two other absolute lymphocyte counts (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.
- ECOG performance status 0 or 1 (see Appendix A)
- Participants must have normal organ and marrow function as defined below:
- total bilirubin within normal institutional limits
- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal
- absolute neutrophil count ≥1000 cells/μL
- 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.
- At least 7 immunizing peptides can be designed.
- Continue to meet inclusion and exclusion criteria for Screening Registration.
- 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.
- 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 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 WBC > 30,000/uL. Factors
contributing to lymphocytosis other than CLL (e.g. infections) should be excluded when
calculating the LDT1.
- Serum immunoglobulin level <400 mg/dL or currently requiring chronic intravenous
immunoglobulin G (IVIG)
- Known chronic infections with HIV, hepatitis B or C (see Study Calendar in Section 10
for screening assays).
- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
- 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 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: a) 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; b) 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;
c) individuals with prostate cancer managed with active surveillance that is not
expected to limit their survival to <10 years.
- Participants with known 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