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

  • STATUS
    Recruiting
  • End date
    May 19, 2025
  • participants needed
    68
  • sponsor
    National Cancer Institute (NCI)
Updated on 23 September 2022
platelet count
cancer
carcinoma
neutrophil count
hormone therapy
HER2
erbb2
breast carcinoma
her2/neu-positive breast cancer
adjuvant chemotherapy
bladder tumor
bladder carcinoma

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.

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 na(SqrRoot) ve 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 na(SqrRoot) ve 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 IL-7 (rhIL-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-I7, a long acting IL-7 cytokine, composed of human IL-7 and a hybrid Fc (hyFc) region to extend half-life.

Objectives

Phase 1: Select optimal biological dose (OBD) of NT-I7 in older subjects with breast, bladder, prostate or a gastrointestinal cancer following chemotherapy.

Phase 1b: Evaluate and quantify the functional impact of NT-I7 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 a gastrointestinal cancer following adjuvant / neo-adjuvant chemotherapy; or metastatic breast, gastrointestinal or prostate cancer after chemotherapy.

Completed a treatment with chemotherapy a minimum of 4 weeks and no more than 12 months prior to entry with no evidence of disease.

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 therapy for their respective diseases.

In Phase 1 part of the study, two dose levels, 720 micro g/kg and 960 micro g/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 na(SqrRoot) ve 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.

Details
Condition Breast Carcinoma, Colorectal Adenocarcinoma, Bladder Carcinoma
Treatment Recombinant human IL-7-hyFc (NT-I7), Vaccine sequence 1, Vaccine sequence 2
Clinical Study IdentifierNCT04054752
SponsorNational Cancer Institute (NCI)
Last Modified on23 September 2022

Eligibility

Yes No Not Sure

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 gastrointestinal cancer following appropriate surgery and adjuvant chemotherapy or following appropriate neoadjuvant chemoradiation/surgery and adjuvant chemotherapy
Stage II or III bladder carcinoma following neo-adjuvant chemotherapy and appropriate surgery or following adjuvant chemotherapy
Stage IV breast, gastrointestinal, or prostate cancer, following surgery and chemotherapy, or chemotherapy alone
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 12 months prior to registration. (Subjects
Adequate organ function, as follows
with hormone receptor positive breast carcinoma maintained on hormonal therapy
AST/ALT: < 3 times upper limit of normal (ULN)
following chemotherapy and radiation are eligible. Subjects with HER2 positive breast
Bilirubin: < 1.5 times ULN
carcinoma maintained on anti-HER2 agents after definitive therapies are also
Absolute Neutrophil Count: > 1000/mm3
eligible)
Platelet count: > 75,000/mm3
Reasonable expectation that no cancer-specific therapy, with the exception noted in
INR/PTT: <1.5 times ULN
the previous criteria, will be given in the subsequent 6 months (PI's discretion)
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
Significant heart disease defined as
Significant coronary arterial disease
Myocardial infarction in the last 6 months, angina in the previous 3 months
Ischemic changes on ECG
Atrio-ventricular block greater than 1st degree, in absence of pacemaker
History of ventricular arrhythmia
Splenomegaly or history of proliferative hematologic disease
Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
Inability to give informed consent
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
Additional exclusion criteria for the Phase-1b part of the study only are as follows
Subjects who received a Td or Tdap immunization in the previous 5 years
Troponin elevation above reference range set by each institution where the
troponin measurement was performed
Latex allergy
QTc (using Fridericia and Framingham correction formula) greater than 480ms
(CTCAE 5.0 grade 1 abnormality is acceptable)
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
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
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)
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
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
months
A history of Guillain-Barre syndrome within six weeks of administration of
previous tetanus toxoid containing vaccines
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