Trial Title:
Responder-derived FMT (R-FMT) and Pembrolizumab in Relapsed/Refractory PD-L1 Positive NSCLC
NCT ID:
NCT05669846
Condition:
Non Small Cell Lung Cancer
Conditions: Official terms:
Carcinoma, Non-Small-Cell Lung
Pembrolizumab
Conditions: Keywords:
Relapsed
Refractory
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Fecal Microbiota Transplant (FMT)
Description:
FMT is a procedure in which fecal matter or stool is collected from a tested donor, mixed
with a saline or other solution, strained and infused into the colon by performing a
colonoscopy and sigmoidoscopy. The FMT consists of introducing normal bacterial flora
contained in the stool collected from a donor into the small intestine. In this case, the
donors are patients with advanced metastatic non-small cell lung cancer (NSCLC) who have
undergone PD-1 therapy (nivolumab or pembrolizumab) and are currently in a durable
remission that is ongoing. The FMT will be performed on Cycle 1 Day 1 and Cycle 3 Day 1
during Treatment Phase 1 and every 9 weeks starting with Cycle 4 Day 1 during Treatment
Phase 2.
Arm group label:
Fecal Microbiota Transplant (FMT) with Pembrolizumab
Intervention type:
Drug
Intervention name:
Pembrolizumab
Description:
Pembrolizumab, 200mg, will be administered as a 30-minute IV infusion every 3 weeks
starting Cycle 1 Day 1 (same day as the FMT), and continue on Day 1 of each 21-day cycle.
Arm group label:
Fecal Microbiota Transplant (FMT) with Pembrolizumab
Other name:
Keytruda
Summary:
This study is to determine if a fecal microbiota transplant (FMT) improves the body's
ability to fight cancer in patients with relapsed/refractory PD-L1 Positive NSCLC.
Detailed description:
The study evaluating the addition of R-FMT to pembrolizumab in PD-1 R/R NSCLC will be
conducted over a 104-week period. Patients with anti-PD-1 R/R NSCLC are eligible to
enroll. Prior exposure to microbiome modulating therapy is exclusionary. Suitable
patients will be identified at the time of progression upon PD-1 monotherapy or PD-1
containing regimens. Patients will undergo a 35-day screening evaluation consisting of
systemic staging scans, tumor biopsy, stool/blood serologic studies to confirm
suitability.
Once enrolled, patients will be seromatched with a suitable donor. Suitable donors are
advanced cancer patients who have undergone PD-1 monotherapy and are currently in durable
remission (median PFS >24 months from initiation of PD-1 therapy) with no ongoing irAE as
delineated below. Patients will receive R-FMT (induction) via colonoscopy on C1D1 and
C3D1. R-FMT (maintenance) via sigmoidoscopy on C4D1 and will be repeated every 9 weeks.
All patients will additionally receive pembrolizumab at 200mg every three weeks. Patients
will be treated until disease progression or intolerable toxicity or completion of 2
years of therapy, whichever comes first.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- The participant (or legally acceptable representative if applicable) provides
written informed consent for the trial.
- Male/female participants who are at least 18 years of age on the day of signing
informed consent.
- Male participants: A male participant must agree to use a contraception as detailed
in Appendix 3 of this protocol during the treatment period and for at least 120 days
after the last dose of study treatment and refrain from donating sperm during this
period.
- Female participants: A female participant is eligible to participate if she is not
pregnant, not breastfeeding, and at least one of the following conditions applies:
Not a woman of childbearing potential (WOCBP) or A WOCBP who agrees to follow the
contraceptive guidance during the treatment period and for at least 120 days after
the last dose of study treatment.
- Histologically or cytologically confirmed diagnosis of stage IV PD-L1+ NSCLC.
Patients with either squamous or non-squamous NSCLC may enroll. Documented PD-L1
status (defined as 1% or greater) as determined by immunohistochemistry with
anti-PD-L1 antibody (IHC 22C3 pharmDx or other FDA approved diagnostic method) from
a core or excisional biopsy (fine needle aspirate is not sufficient). Patients with
small cell, large cell, neuroendocrine and/or sarcomatoid NSCLC are excluded.
- Participants must have progressed on treatment with an anti-PD(L)1 ICI administered
either as monotherapy or in combination with other checkpoint inhibitors or other
standard/investigational therapies. PD-1 treatment progression is defined by meeting
all the following criteria:
- Has received at least 2 doses of an approved anti-PD(L)1 ICI administered as a
single agent, in combination with chemotherapy, and/or in combination with
other investigational therapy.
- Participants who progressed on/within 3 months of adjuvant therapy with
anti-PD(L)1 ICI will eligible.
- Demonstrated disease progression after anti-PD-1/L1 as defined by RECIST v1.1.
The initial evidence of PD is to be confirmed by a second assessment no sooner
than 4 weeks from the date of the first documented PD.
- Progressive disease has been documented within 12 weeks from the last dose of
anti-PD-1/anti-PD-L1 mAb.
- NOTE: Progressive disease must be determined as above.
- NOTE: Only patients with primary progressive disease wherein best response to
anti-PD(L)1 therapy is PD or SD less than/equal to 6 months are eligible. If
multiple anti-PD(L)1 lines were received, the patient is eligible if the
response is similar (PD or SD less than/equal to 6 months) for all anti-PD(L)1
lines of therapy.
- NOTE: This determination is made by the treating investigator. Once PD is
confirmed, the initial date of PD documentation will be considered the date of
PD.
- NOTE: Anti-PD(L)1 ICI need not be the most recent line of therapy administered.
- Patients with CNS disease are eligible if CNS metastases are treated and deemed
stable prior to date of enrollment.
- NOTE: All patients will undergo CNS imaging at the time of Screening. Patients
with treated brain metastases will need repeat CNS imaging to document
stability.
- NOTE: Stability is defined based on appearance of treated lesions on a
contrast-enhanced CT or MRI brain study performed as part of screening by
radiologist, radiation oncologist or neurosurgeon (whichever is most
appropriate); absence of new or enlarging brain metastases; and no longer
requiring systemic steroids (≤ 10 mg/day prednisone or equivalent) for at least
one week prior to enrollment.
- NOTE: The contrast-enhanced CT or MRI brain imaging study should be performed
no sooner than 2 weeks after most recent surgical and/or radiological
intervention.
- NOTE: If lesions were discovered during Screening, the patient may be eligible
if the lesions are treated and stable based on the above criteria.
- NOTE: Patients with leptomeningeal involvement (leptomeningeal enhancement on
MRI/CT imaging and/or positive CSF cytology) are excluded regardless of
stability.
- Prior treatment(s)
- NOTE: Prior anti-CTLA-4 ICI is allowed but not required.
- NOTE: Patients with known oncogenic driver (including but not limited to EGFR,
ALK, ROS, MET alterations) must have received and progressed past
driver-specific therapy.
- Willingness to repeatedly receive FMT administered endoscopically (colonoscopy or
sigmoidoscopy) following necessary bowel preparation pre-procedure.
- NOTE: Understands infectious risks associated with FMT administration. Although
FMT infusate has been screened for bacteria, viruses, fungi and parasites there
is a risk of transmission of known and unknown infectious organisms contained
in the donor stool. Post-FMT bacteremia (e.g., E. coli), sepsis and fatal
events may rarely occur.
- NOTE: Understands non-infectious risks associated with FMT administration.
Possible allergy and/or anaphylaxis to antigens in donor stool. Theoretical
risk of developing disease possibly related to donor gut microbiota including
but not limited to: obesity, metabolic syndrome, cardiovascular disease,
autoimmune conditions, allergic/atopic disorders, neurologic disorders,
psychiatric conditions and malignancy.
- NOTE: Understand risks associated with endoscopy (colonoscopy or sigmoidoscopy)
including risk of infection transmission, colonic perforation, aspiration
pneumonia, and death.
- NOTE: Understand that data regarding the long-term safety risk of FMT are
lacking.
- Presence of measurable disease based on RECIST 1.1. Patients need to have at least
one measurable lesion and a separate lesion for biopsy. Patients with only 1 lesion
may be enrolled after discussion with Sponsor-Investigator. Lesions situated in a
previously irradiated area are considered measurable if progression has been
demonstrated in such lesions.
- Able to provide newly obtained core or excisional biopsy of a tumor lesion not
previously irradiated to undergo tumor biopsy (core, punch, incisional or
excisional). Biopsy must meet minimal sampling criteria.
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
- Life expectancy of at least 12 weeks, as estimated using the Gustave Roussy Immune
Score (GRIm-Score); i.e., must meet no more than 1 of the following criteria:
- Albumin < 3.5 g/dL
- Lactate dehydrogenase (LDH) > ULN
- Neutrophils-to-lymphocyte ratio (NLR) > 6
- Have adequate organ function as defined below. Specimens must be collected within 28
days prior to the start of study intervention.
- Absolute neutrophil count (ANC) ≥1500/µL
- Platelets ≥100 000/µL
- Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L (Criteria must be met without
erythropoietin dependency and without packed red blood cell (pRBC) transfusion
within last 2 weeks)
- Creatinine OR measured or calculated creatinine clearance (GFR can also be used
in place of creatinine or CrCl) (Creatinine clearance (CrC) should be
calculated per institutional standard) ≤1.5 x ULN OR ≥30 mL/min for participant
with creatinine levels >1.5 x institutional ULN
- Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total
bilirubin levels >1.5 × ULN
- AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver
metastases)
- International normalized ratio (INR) OR prothrombin time (PT); Activated
partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving
anticoagulant therapy as long as PT or aPTT is within therapeutic range of
intended use of anticoagulants
- Criteria for patients with hepatitis B and C:
- Screening for hepatitis B and C are required.
- For hepatitis B positive patients: Patients who are hepatitis B positive (i.e.,
HBsAg positive) or have a history of history of hepatitis B (i.e., HBcAb
positive, or history of documented hepatitis B infection) are eligible if they
have received hepatitis B directed antiviral therapy for at least 4 weeks and
have undetectable HBV viral load (HBV DNA) prior to enrollment. Participants
should remain on antiviral therapy throughout study intervention and follow
local guidelines for HBV antiviral therapy post completion of study
intervention.
- For hepatitis C positive patients: Patients who are hepatitis C positive (i.e.,
HCV antibody reactive) or have a history of history of hepatitis C (i.e.,
history of documented hepatitis C infection) are eligible if they have received
and completed hepatitis C directed antiviral therapy at least 4 weeks and have
undetectable HCV viral load (HCV RNA) prior to enrollment.
Exclusion Criteria:
- Diagnosis of non-squamous/adenocarcinoma NSCLC histologies including small cell,
large cell, neuroendocrine and/or sarcomatoid histologies.
- Prior therapies:
- Receipt of prior agent(s) targeting the intestinal microbiome including but not
limited to: FMT, defined bacterial consortia, single bacterial species and/or
microbiota derived peptides.
- Prior chemotherapy, targeted therapy, and/or small molecule therapy within 2
weeks (or 4 half-lives) prior to study Day 1.
- Prior radiotherapy within 2 weeks of start of study intervention. Participants
must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis. A 2-week washout is
permitted for palliative radiation (≤2 weeks of radiotherapy) to disease
including CNS disease.
- Presence of an absolute contraindication(s) to FMT administration:
- Toxic megacoon
- Severe dietary allergies (e.g., shellfish, nuts, seafood)
- Inflammatory bowel disease
- Patients who have not adequately recovered (i.e., ≤Grade 1 or at baseline or ≤Grade
2 endocrinopathy) from adverse events (AEs) due to a previously administered agent.
- A WOCBP who has a positive urine pregnancy test at Screening. If the urine test is
positive or cannot be confirmed as negative, a serum pregnancy test will be
required.
- 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), SARS-CoV-2 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.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 14 days prior to the first dose of study drug.
- Has active autoimmune disease that has required systemic treatment in the past 2
years (i.e., with use of disease modifying agents, corticosteroids or
immunosuppressive drugs).
--- NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
not considered a form of systemic treatment and is allowed.
- Concurrent non-hematologic malignancy within 3 years of data of first planned dose
of therapy except for tumors with a negligible risk of metastasis and/or death as
defined below:
- Adequately treated non-invasive malignancies including but not limited to
melanoma in situ (MIS), cutaneous squamous cell carcinoma (cSCC), in situ cSCC,
basal cell carcinoma (BCC), CIS of cervix, or DCIS/LCIS of breast.
- Low-risk early-stage prostate adenocarcinoma (T1-T2a N0 M0 and Gleason score ≤6
and PSA ≤10 ng/mL) for which the management plan is active surveillance, or
prostate adenocarcinoma with biochemical-only recurrence with documented PSA
doubling time of > 12 months for which the management plan is active
surveillance.
- Indolent hematologic malignancies for which the management plan is active
surveillance including but not limited to CLL/indolent lymphoma. Patients with
high-risk hematologic malignancies (CML, ALL, AML, Hodgkin's or non-Hodgkin's
lymphoma) are excluded even if the management plan is active surveillance.
- Active (i.e., symptomatic or growing) central nervous system (CNS) metastases.
- NOTE: Participants with previously treated brain metastases may participate
provided they are radiologically stable, i.e., without evidence of progression
for at least 2 weeks by repeat imaging (note that the repeat imaging should be
performed during Screening), clinically stable and without requirement of
steroid treatment for at least 14 days prior to first dose of study
intervention.
- NOTE: Patients with leptomeningeal disease are excluded.
- Has severe hypersensitivity (≥Grade 3) to anti-PD(L)1 inhibitor.
- Has a systemic disease that requires systemic pharmacologic doses of corticosteroids
greater than 10 mg daily prednisone (or equivalent).
- NOTE: Participants who are currently receiving steroids at a dose of ≤10 mg
daily do not need to discontinue steroids prior to enrollment.
- NOTE: Participants that require topical, ophthalmologic, injected and/or
inhalational steroids are not excluded from the study.
- NOTE: Participants with hypothyroidism stable on hormone replacement or
Sjogren's syndrome are not excluded from the study.
- NOTE: Participants who require active immunosuppression (greater than steroid
dose discussed above) for any reason are excluded from the study.
- Has a history of interstitial lung disease or active, non-infectious pneumonitis
that required steroids or has current pneumonitis.
- Has a history of non-infectious myocarditis or symptomatic cardiac co-morbidities
requiring active management.
- NOTE: Patients with a history of symptomatic congestive heart failure (New York
Heart Association Functional Classification III or IV) are excluded.
- NOTE: Patients with a history of unstable angina, serious uncontrolled cardiac
arrhythmia, or myocardial infarction 6 months prior to study entry are
excluded.
- Active infections:
- Any active infection requiring systemic therapy.
- Active TB (Bacillus Tuberculosis).
- Active COVID-19 infection and/or exposure to SARS-CoV-2: Positive SARS-CoV-2
result on nasopharyngeal and/or stool specimens (by RT-PCR test); Active
COVID-19 infection (per CDC guidelines); Exposure to active COVID-19 infected
patient (as confirmed using SARS-CoV-2 RT-PCR test or other approved test) as
defined per CDC guidelines.
- Active human immunodeficiency virus (HIV) infection. Patients will be evaluated
for HIV during screening.
- Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV
DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV
RNA) infection.
- Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with the
participant's participation for the full duration of the study, or is not in the
best interest of the participant to participate, in the opinion of the treating
investigator.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting with the Screening visit through 120 days
after the last dose of trial treatment.
- Has had an allogenic tissue/solid organ transplant.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
UPMC Hillman Cancer Center
Address:
City:
Pittsburgh
Zip:
15232
Country:
United States
Contact:
Last name:
Amy Rose, RN, BSN
Phone:
412-647-8587
Email:
kennaj@upmc.edu
Contact backup:
Last name:
Diwakar Davar, MD, PhD
Start date:
November 30, 2024
Completion date:
October 31, 2029
Lead sponsor:
Agency:
Diwakar Davar
Agency class:
Other
Collaborator:
Agency:
Gateway for Cancer Research
Agency class:
Other
Source:
University of Pittsburgh
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05669846
