Conditions

• Colorectal Cancer
• Peritoneal Metastases
• Carcinomatosis

Eligibility

Eligible Ages

Over 18 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

Eligibility Criteria

- Subjects must be 18 years or older. Because no dosing or adverse event data are
currently available on the use of IP/IV TROP2 CAR/IL-15 TGFBR2 KO NK Cell Therapy +
Cetuximab in participants 3 liver metastases, >5 lung metastases, or >8 metastases
combined between all extraperitoneal sites will not be included even in the setting
of measurable peritoneal disease. If a participant has peritoneal-predominant
disease with ≤ 8 total extraperitoneal metastases, they may be included at the
discretion of the PI.

- Subjects must be at least 4 weeks from their last dose of systemic cytotoxic
chemotherapy at the time of their diagnostic laparoscopy (DL)/IP catheter placement
or 6 weeks if the chemotherapy regimen included Bevacizumab. Participants must be at
least 4 weeks from their last dose of systemic cytotoxic chemotherapy at the time of
their lymphodepleting (LD) chemotherapy.

- Subjects must be willing to undergo DL and IP catheter placement along with
scheduled peritoneal fluid/peripheral blood draws and biopsies.

- Subjects must have adequate organ function as defined in the following table.
Specimens must be collected within 10 days prior to the start of study treatment.

- Participant s must have histologically confirmed microsatellite stable (MSS)
CRC-related PM that is not amenable to curative resection (participant determined
not to be a candidate for CRS +/- HIPEC by surgical oncologist with expertise in
peritoneal surface malignancies) and for which standard curative treatment is no
longer effective (they have progressed through at least one line of standard
systemic chemotherapy and/or are intolerant of systemic chemotherapy in the opinion
of their primary medical oncologist). • MSS status must be confirmed either by
immunohistochemistry (IHC) or polymerase chain reaction (PCR)-based genetic
analysis. Participants with MSI-H tumors are ineligible. • Participant must have
never undergone a prior HIPEC operation (CRS without HIPEC is OK) • Participant s
with a prior or concurrent malignancy whose natural history or treatment does not
interfere with the safety or efficacy assessment of the investigational regimen are
eligible for this trial.

- Participants with known history or current symptoms of cardiac disease, or history
of treatment with cardiotoxic agents, should have a clinical risk assessment of
cardiac function using the New York Heart Association Functional Classification. To
be eligible for this trial, participant s should be class 2B or better.

- Women of childbearing potential (WOCBP): The effects of CAR NK therapy on the
developing human fetus are unknown. For this reason and because lymphodepleting (LD)
chemotherapy agents as well as other therapeutic agents used in this trial are known
to be teratogenic, women of child-bearing potential and men must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence)
prior to study entry and for the duration of study participation and 4 months after
completion of CAR NK therapy administration. (Refer to Pregnancy Assessment Policy
MD Anderson Institutional Policy # CLN1114). This includes all female participant s,
between the onset of menses (as early as 8 years of age) and 55 years unless the
participant presents with an applicable exclusionary factor which may be one of the
following:

- Postmenopausal (no menses in greater than or equal to 12 consecutive months). o
History of hysterectomy or bilateral salpingo-oophorectomy.

- Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who
have received Whole Pelvic Radiation Therapy).

- History of bilateral tubal ligation or another surgical sterilization procedure.

Approved methods of birth control are as follows: Hormonal contraception (i.e. birth
control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device
(IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or
injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity
for the total duration of the trial and the drug washout period is an acceptable
practice; however periodic abstinence, the rhythm method, and the withdrawal method are
not acceptable methods of birth control. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform her
treating physician immediately. See Appendix 1 for more details.

- Men treated or enrolled on this protocol must also agree to use adequate
contraception prior to the study, for the duration of study participation, and 4
months after completion of TROP2 CAR/IL-15 TGFBR2 KO NK cells therapy
administration.

Exclusion Criteria

- Pregnant, breastfeeding, or expecting to conceive within the projected duration of
the study, starting with screening visit through 4 months after last dose of trail
treatment (TROP2 CAR/IL-15 TGFBR2 KO NK cell therapy). If a WOCBP has a positive
urine pregnancy test within 72 hours prior to administration of LD chemotherapy that
cannot be confirmed as negative, a serum pregnancy test will be required.

- Participants with BRAFV600E mutated tumors (determined by Next Generation
Sequencing, NGS) will be excluded.

- Has received systemic anti-cancer therapy within 4 weeks of their scheduled
diagnostic laparoscopy (DL)/IP catheter placement or 6 weeks if the regimen included
Bevacizumab. Or has received systemic chemotherapy of any kind within 4 weeks prior
to the time of their lymphodepleting (LD) chemotherapy.

- Participants must have recovered from all AEs due to previous therapies to Grade ≤1
or baseline. Participants with Grade ≤2 neuropathy, alopecia, or other AEs may be
deemed eligible at the discretion of the PI. If a participant received major
surgery, they must have recovered adequately from the toxicity and/or complications
from the intervention prior to starting study treatment.

- Has received prior radiotherapy within 2 weeks of the start of study intervention
(DL). Participants must have recovered from all radiation-related toxicities, not
require corticosteroids, and not have had radiation pneumonitis. A 1-week washout if
permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous
system (CNS) disease.

- Has received a live vaccine within 30 days prior to the initiation of LD
chemotherapy. 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), and typhoid vaccines. Seasonal influenza and
COVID 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.

- Is currently receiving another investigational agent or has used an investigational
device within 6 weeks prior to the first dose of study intervention. Participants
who have entered the follow-up phase of an investigational study may participate as
long as it has been 6 weeks after the last dose of the previous investigation agent.

- Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy (in
dosing exceeding 10mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose LD.

- High-volume extra-peritoneal visceral metastases to include but are not limited to,
high volume (>3) liver metastases, high volume (>5) lung metastases, CNS metastases
(any number) and/or carcinomatous meningitis, bone metastases (any number) will be
excluded. Any participant s with >8 total metastases combined between all visceral
extraperitoneal sites will also be excluded. Low volume liver (≤3) and/or lung (≤5)
metastases that have been treated, are amendable to locoregional therapy, and are
not an immediate threat to life may be included at the discretion of the PI if the
total number of visceral extraperitoneal metastases remains ≤ 8. Individuals with
nodal metastases and/or abdominal wall metastases similarly may be included at the
discretion of the PI.

- Active autoimmune disease that has required systemic treatment in the past 2 months
(i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive
drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed.

- History of interstitial lung disease that required steroids or has current
pneumonitis/interstitial lung disease.

- Serious active infection requiring intravenous systemic therapy.

- Uncontrolled Human Immunodeficiency Virus (HIV) infection. Participants with HIV who
have an undetectable viral load and a CD4 count of at least 400 cells/mm3 may
participate.

- Known Hepatitis B Virus (HBV) not on suppressive therapy or with detectable viral
load on suppressive therapy. If undetectable viral load on suppressive therapy, OK
to participate.

- Known Hepatitis C Virus who has not been treated or cured, or who is currently being
treatment with a detectable viral load. If cured or being treated with an
undetectable viral load, OK to participate.

- Known history of active Tuberculosis (TB).

- History or current evidence of any condition, therapy, or laboratory abnormalities
that might confound the results of the study, interfere with the subject's
participation for the full duration of the study, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.

- Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial.

- Has had allogeneic tissue/solid organ transplant.

- Clinically significant cardiovascular disease within 12 months from the first dose
of study intervention, including New York Heart Association (NYHA) Class III or IV
congestive heart failure, unstable angina, myocardial infarction, cerebral vascular
event, or cardiac arrhythmia associated with hemodynamic instability. Note:
medically controlled arrhythmia would be permitted.

- Prolonged QTcF interval to >480 ms.

- Bleeding or thrombotic disorders or subjects at risk of severe hemorrhage. Subject
with known deep vein thrombosis/pulmonary embolism that are under appropriate
anticoagulation treatment are eligible.

- Radiographic distribution of disease that in the investigator's opinion would impart
excessive risk to participation to this protocol.

- Active peritonitis or diverticulitis.

- Medical or surgical history that in the treating physician's opinion would make the
subject not a suitable candidate for intraperitoneal therapy. Examples would include
surgically documented extensive intraperitoneal adhesions, prior HIPEC operation, or
large volume ascites.

- History of severe hypersensitivity reaction with biologic therapies (e.g. monoclonal
antibodies).

Recruiting Locations

Study Contact

Detailed Description

Primary Objective and Endpoints Objective: Determine the safety, and Maximum Tolerated Dose (MTD), Recommended Phase 2 Dose (RP2D), schedule of iterative delivery of dual administration of IP/IV TROP2 CAR/IL-15 TGFBR2 KO NK cells Cell Therapy + IV Cetuximab