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BRIEF TITLE: Enhancement of Immune Reconstitution and Vaccine Responses With Administration of Recombinant Human IL-7-hyFc (NT-I7) in Older Subjects Following Chemotherapy

A Phase 1/1b Study of Enhancement of Immune Reconstitution and Vaccine Responses With Administration of Recombinant Human IL-7-hyFc (NT-I7) in Older Subjects Following Chemotherapy


  • Org Study ID: 190134
  • Secondary ID: 19-C-0134
  • NCT ID: NCT04054752
  • NCT Alias:
  • Sponsor: National Cancer Institute (NCI) - NIH
  • Source: National Institutes of Health Clinical Center (CC)

Brief Summary

Background: People with cancer, and especially older people, have a weakened immune system (the defense system of the body). This is often caused by the treatments for cancer. Older cancer survivors are therefore more prone to getting infections, some of which are preventable through vaccines. But because their immune systems are weakened, their response to vaccines is poor. Researchers want to see if a new drug, NT-I7, can help. Objective: To see if NT-I7 can boost the immune system. Eligibility: Adults 60 and older who have recently finished chemotherapy for breast, colorectal, or bladder cancer. Design: Participants will be screened with a physical exam, medical history, and blood and urine samples. Their heart s electrical activity will be checked. They will have an ultrasound of their spleen. They may give a tissue sample from a previous biopsy. Participants in phase 1a of the study will get 1 dose of NT-I7. It will be given by injection with a needle into the muscle of the upper arm, thigh, or buttocks. Participants in phase 1b will get 5 vaccines over a few months. They may get an optional booster and/or 6th vaccine. They will also get NT-I7. Participants will repeat the screening tests during the study. They may get a peripheral intravenous catheter in a vein in their hand or arm for blood draws. Participants may have apheresis. For this, blood is taken from an arm vein. The white blood cells are separated from the blood. The rest of the blood, minus the white blood cells, is returned into a vein in the other arm. A catheter may be used. Participants will have follow-up visits for 1 year.

Detailed Description


Background:

- Interleukin-7 is a homeostatic cytokine with a critical role in lymphoid homeostasis
through which it exerts its immune-restorative effects, particularly re-expansion of the
naive and memory T-cell subsets.

- The clinical implications of the kinetics, nature and extent of immune reconstitution
defects following standard or ablative chemotherapy in older adults with cancer (in
particular the lack of reconstitution of large pools of naive T-cell with broad
repertoire diversity and of memory T-cells) are not well characterized.

- As chemotherapy often induces only temporary complete or partial disease responses but
no cure, candidates for novel immunotherapy strategies may be significantly impeded in
their responses to active immunotherapy attempts, the therapeutic potential of which is
becoming increasingly utilized.

- Recombinant human TL-7 (rhTL-7) may play a role in immune reconstitution and immune
enhancement in various circumstances of immune insufficiency in older individuals
following chemotherapy or in the context of enhancing cancer immunotherapy or during
immune senescence.

- Elderly cancer survivors are vulnerable to vaccine-preventable diseases and are known to
have poor anti-vaccine-specific immune responses. Effective prevention of communicable
diseases is important for cancer survivorship.

- This study will use NT-T7, a long acting TL-7 cytokine, composed of human TL-7 and a
hybrid Fc (hyFc) region to extend half-life.

Objectives:

- Phase 1: Select optimal biological dose (OBD) of NT-T7 in older subjects with breast,
bladder, and colorectal cancer following chemotherapy.

- Phase 1b: Evaluate and quantify the functional impact of NT-T7 therapy on specific
immune responses to selected vaccines in older subjects following chemotherapy.

Eligibility:

- Adults greater than or equal to 60 year of age.

- Diagnosis of non-metastatic breast, bladder or colorectal cancer following
adjuvant/neo-adjuvant chemotherapy.

- Completed a treatment with chemotherapy a minimum of 4 weeks prior to entry.

- Reasonable expectation that no cancer-specific therapy will be given in the subsequent 6
months.

Design:

- Subjects will be enrolled into this single center Phase 1/1b study following the
specific or their respective diseases.

- In Phase 1 part of the study, two dose levels, 720 microgram/kg and 960 microgram/kg,
will be compared. Six subjects will be enrolled in each dose level, and a single dose of
NT-I7 will be delivered intramuscularly. The purpose of this part of the study is to
select the OBD.

- OBD is defined as the dose that yields the greatest rise in peak absolute total T-cell
counts (peak value at any timepoint during the first 28 days post NT-I7 administration)
with corresponding rise in naive subsets of CD4+ and CD8+ T cells without accompanying

substantial toxicities. Absolute increase is a delta between the baseline counts and the peak
counts within each subject.

-Once OBD is determined, the Phase 1b portion of this study will begin. Subjects will undergo
immunizations with various antigens, randomized to be administered either before or after a
single dose of NT-I7 at OBD. This inter-subject randomization of the order in

which the immunizations are administered (according to the Sequence 1 or to the Sequence 2
schedule) will allow all immunocompromised subjects entered on the Phase 1b portion of the
study to receive NT-I7.

- The vaccines, randomly assigned to be administered before NT-I7 therapy are administered
six weeks before the administration of NT-I7 therapy.

- The vaccines, randomly assigned to be administered after NT-I7 therapy are administered
3 weeks after NT-I7 injection.

Overal Status Start Date Phase Study Type
Recruiting November 24, 2020 Phase 1 Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: Phase 1: Safety of NT-I7 in elderly patients after chemotherapy

Primary Outcome 1 - Time Frame: 28 days after treatment

Primary Outcome 2 - Measure: Phase 1b: Evaluate and quantify if NT-I7 at optimal biological dose (OBD) has impacts on specific immune responses to vaccines

Primary Outcome 2 - Time Frame: day 42 and day 106

Condition:

  • Breast Carcinoma
  • Colorectal Adenocarcinoma
  • Bladder Carcinoma

Eligibility

Criteria:
- INCLUSION CRITERIA:

- Age greater than or equal to 60 years

- Documentation of positive diagnosis based on pathology/histology report (no need for
archival tissue or new biopsy) for any of the following:

- Stage I-III breast carcinoma following neo-adjuvant/adjuvant chemotherapy and
appropriate surgery and/or radiotherapy.

- Stage II or III colorectal adenocarcinoma following appropriate surgery and
adjuvant chemotherapy or following appropriate neoadjuvant chemoradiation/surgery
and adjuvant chemotherapy.

- Stage II bladder carcinoma following neo-adjuvant chemotherapy and appropriate
surgery or following adjuvant chemotherapy.

NOTE: Appropriate therapy" for each disease must be consistent with NCCN Clinical Practice
Guidelines in Oncology available at the time of treatment in the opinion of the
investigator (http://www.nccn.org/professionals/physician_gls/f_guidelines.asp)

- Completed cancer specific therapy (including surgery, radiotherapy and/or systemic
therapy) at least 4 weeks and no more than 6 months prior to registration. (Subjects
with hormone receptor positive breast carcinoma maintained on hormonal therapy
following chemotherapy and radiation are eligible. Subjects with HER2 positive breast
carcinoma maintained on anti-HER2 agents after definitive therapies are also
eligible).

- Reasonable expectation that no cancer-specific therapy, with the exception noted in
the previous criteria, will be given in the subsequent 6 months (PI's discretion).

- Adequate organ function, as follows:

- AST/ALT: < 3 times upper limit of normal (ULN)

- Bilirubin: < 1.5 times ULN

- Absolute Neutrophil Count: > 1000/mm3

- Platelet count: > 75,000/mm3

- INR/PTT: <1.5 times ULN

- Serum Creatinine: <1.5 times ULN

- CPK: <2.5 times ULN

- Serum albumin: greater than or equal to 3g/dL

- Serum electrolytes: within normal limits

- Karnofsky performance status greater or equal to 70%

- Effects of NT-I7 on the developing human fetus are unknown. For these reasons the
following measures apply:

- Subjects enrolled on the study must not be planning to father children within the
projected duration of the trial, starting with the pre-screening/screening visit
through 90 days after the administration of NT-I7.

- Men with partners of childbearing potential (defined as any female who has
experienced menarche and who has not undergone successful surgical sterilization
or who is not postmenopausal (i.e., amenorrheic for greater than or equal to 12
months without alternative medical cause) must use effective contraception prior
to study entry, and for 90 days after the administration of NT-I7.

- Should a woman become pregnant or suspect she is pregnant while her partner is
participating in this study, the study participants' treating physician should be
informed immediately.

EXCLUSION CRITERIA:

- Subjects who are receiving any other investigational agents

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Significant heart disease defined as:

- Significant coronary arterial disease

- Myocardial infarction in the last 6 months, angina in the previous 3 months

- Troponin elevation above reference range set by each institution where the
troponin measurement was performed.

- Ischemic changes on ECG

- Atrio-ventricular block greater than 1st degree, in absence of pacemaker

- QTc (using Fridericia and Framingham correction formula) greater than 480ms
(CTCAE 5.0 grade 1 abnormality is acceptable)

- History of ventricular arrhythmia

- Left Ventricular Ejection Fraction of less than 50% determined by
echocardiography

- Positive serology for HTLV-I or HIV, or serology findings indicative of ongoing
infection with hepatitis A, hepatitis B, or hepatitis C. Subjects with serology
findings indicative of previous exposure to hepatitis A or B vaccination will not be
excluded from Phase 1 part of the study but will be excluded from Phase 1b part of the
study (see below for additional exclusion criteria for the Phase-1b part of the study
only).

- History of autoimmune disease EXCEPT for the following: subjects with vitiligo or
endocrine disease controlled by replacement therapy including diabetes, thyroid, and
adrenal disease may be enrolled

- Subjects requiring chronic immunosuppressive therapy (including corticosteroids above
physiologic replacement dosage) for any medical condition. We will permit 1) systemic
corticosteroids at physiologic replacement dosage which are not to exceed 10 mg/day of
prednisone or an equivalent, 2) intranasal or inhaled corticosteroids, 3)
intraarticular injection of corticosteroids, 4) topical corticosteroids, 5) or a
short-term use of systemic corticosteroids greater than 10 mg/day of prednisone or an
equivalent for 10 days or less.

- Splenomegaly or history of proliferative hematologic disease

- Prior allogeneic hematopoietic stem cell transplantation or solid organ
transplantation

- History of medical or psychiatric disease, or cognitive impairment, which, in the view
of the principal investigator would preclude safe treatment

- Serious bleeding diathesis based on clinical history of significant bleeding
attributed to coagulation/bleeding disorders, documentation of abnormal coagulation
factors/platelet function studies at the discretion of PI, or those who are on
therapeutic anticoagulation

- Inability to give informed consent

- Subjects who have received immune checkpoint inhibitors in the previous 12 months, or
subjects who have received immunomodulatory drugs in the previous 4 weeks for any
medical indications. Subjects who have received intravesical BCG administration for
non-muscle invasive bladder cancer will be included in this study (i.e., not one of
exclusion criteria).

- Additional exclusion criteria for the Phase-1b part of the study only are as follows:

- Known hypersensitivity to any of the following: diphtheria toxoid, neomycin,
polymixin B, streptomycin, 2 phenoxyethanol, formaldehyde, aluminum hydroxide,
yeast

- Previous exposure to Hepatitis A or B vaccines or history of hepatitis A or B
infection

- Subjects who received a Td or Tdap immunization in the previous 5 years

- History of anaphylaxis or serious allergic reactions to previous administration
of any of the vaccines

- Subjects who had received one or more doses of the PPSV23 vaccine in the previous
12 months

- Latex allergy

- A history of Guillain-Barre syndrome within six weeks of administration of
previous tetanus toxoid containing vaccines.
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Gender: All

Minimum Age: 60 Years

Maximum Age: N/A

Healthy Volunteers: No

Official Information

Name: Ronald E Gress, M.D.

Role: Principal Investigator

Affiliation: National Cancer Institute (NCI)

Overall Contact

Name: Ronald E Gress, M.D.

Phone: (240) 760-6167

Email: gressr@mail.nih.gov

Link: NIH Clinical Center Detailed Web Page

Location

Facility Status Contact
National Institutes of Health Clinical Center
Bethesda, Maryland 20892
United States
Recruiting For more information at the NIH Clinical Center contact National Cancer Institute Referral Office
888-624-1937