Phase II Study Evaluating the Efficacy of M9241 in Combination With Hepatic Artery Infusion Pump (HAIP) and Systemic Therapy for Subjects With Metastatic Colorectal Cancer or Intrahepatic Cholangiocarcinoma

• Status: Not yet recruiting
• Trial end date: 2028-12-31
• Target enrollment: 0
• Participant gender: All

Summary

Background:

• Regional chemotherapy for hepatic malignancies takes advantage of the fact that tumors are perfused almost exclusively by the hepatic artery and, that the agent used (Floxuridine, FUDR) has a 95% first-pass metabolism by the liver.

• Early clinical trials performed during the 1970's and 1980's demonstrated impressive response rates that led to the adoption of hepatic artery infusion pump chemotherapy (HAIP) at select centers; however, little has changed in the ensuing decades with respect to regional therapy for the liver, although there has been continued and even renewed interest.

• Dose reductions of FUDR are common after several treatments, which has limited both the magnitude and duration of treatment responses in many cases.

• We posit that the logical and much-needed next step in regional therapy is to take advantage of the FUDR-induced tumor necrosis with an agent able to activate local tumor immunity for a synergistic effect.

• M9241 (NHS-IL12) is an immunocytokine composed of two IL-12 heterodimers, each fused to the H-chain of the NHS76 antibody. The NHS76 IgG1 antibody has affinity for both single- and double-stranded DNA (dsDNA), and targets regions of tumor necrosis where DNA has become exposed. M9241 targets necrotic areas of the tumor and activates immune cells in the tumor microenvironment to induce a Th1 polarization of lymphocytes and the release of IFN-gamma. IFN-gamma in turn induces a host of immunomodulatory effects that contribute to robust antitumor responses.

• Data from a recent Phase I study demonstrate that subcutaneous administration of M9241 is safe and a MTD has been determined. Moreover, preclinical models indicate that M9241 synergizes with therapies able to effectively induce tumor necrosis, which may also minimize toxicity by limiting off-target exposure.

Objective:

-To determine the overall response rates in subjects with unresectable metastatic colorectal cancer (mCRC) and intrahepatic cholangiocarcinoma (ICC) treated with M9241 in combination with HAIP therapy

Eligibility:

• Histologically or cytologically confirmed colorectal adenocarcinoma metastatic to the liver (cohort 1) or unresectable intrahepatic cholangiocarcinoma (cohort 2).

• No evidence of extrahepatic metastases

• Subjects must have received first-line systemic chemotherapy.

• Age >= 18 years.

Design:

-Open label, single center, non-randomize Phase II study

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Cancer Institute (NCI)
• Treatments: Dexamethasone; Floxuridine; Fluorouracil; Gemcitabine; Irinotecan; Leucovorin; Oxaliplatin

Criteria

• INCLUSION CRITERIA:

Inclusion Criteria- All Cohorts

• Age >= 18 years.

• Negative serum or urine pregnancy test at screening for women of childbearing potential (WOCBP).

NOTE: WOCBP is defined as any female who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal. WOCBP must have a negative pregnancy test (HCG blood or urine) during screening

• Women of child-bearing potential and men must agree to use highly effective contraception prior to study entry, for the duration of study participation and for 3 months after completion of study treatment. Highly effective birth control (failure rate of less than 1%), e.g., intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner and sexual abstinence. The use of condoms by male subjects is required unless the female partner is permanently sterile.

• Breastfeeding subject must agree to discontinue breastfeeding.

• Arterial anatomy on CT angiogram amenable to placement of the HAIP.

• Subject must sign the informed consent form to participate in this study.

• HIV-positive subjects may be considered for this study only if they have an undetectable viral load.

• Subjects must agree to co-enroll on the Surgical Oncology Program s tissue collection protocol 13C0176, Tumor, Normal Tissue and Specimens from Patients Undergoing Evaluation or Surgical Resection of Solid Tumors

• Subject s liver metastases must not be amenable to resection/ablation to No Evidence of Disease (NED) in one stage.

• Subject must be able to tolerate systemic chemotherapy at initiation of study treatment as outlined below (mCRC: FOLFOX or FOLFIRI; ICC: GemOx).

Inclusion Criteria-Metastatic Colorectal Carcinoma

• Subjects must have histologically or cytologically confirmed diagnosis of colorectal adenocarcinoma metastatic to the liver (cohort 1), confirmed by the Laboratory of Pathology, NCI.

• Subjects must have measurable liver metastatic disease

• Subjects must have received 1st line systemic chemotherapy

• ECOG performance status <= 1

• Subjects must have adequate organ and marrow function as defined below:

• leukocytes > 3,000/mcL

• absolute neutrophil count > 1,500/mcL

• platelets > 90,000/mcL

• hemoglobin > 9 g/dL

• total bilirubin < 1.5 X institutional upper limit of normal

• AST(SGOT)/ALT(SGPT) < 2.5 X institutional upper limit of normal OR eGFR within normal as predicted by the CKD-EPI equation > 60 mL/min/1.73 m2.

Inclusion Criteria-Intrahepatic Cholangiocarcinoma

• Subjects must have histologically or cytologically confirmed diagnosis of intrahepatic cholangiocarcinoma confined to the liver (cohort 2), confirmed by the Laboratory of Pathology, NCI. Archival tumor sample may be used but if archival tissue is not available or is not adequate, tissue biopsy will be required

• Clinical or radiographic evidence of metastatic disease to regional (porta hepatis) lymph nodes will be allowed, provided it is amenable to resection.

• Subjects must have radiographically measurable disease

• Disease must be considered unresectable at the time of preoperative evaluation.

• Subjects must have received 1st line systemic chemotherapy

• ECOG performance status <= 1.

• Subjects must have adequate organ and marrow function as defined below:

• leukocytes >= 2,000/ mm(3)

• absolute neutrophil count > 1,500/mcL

• platelets >= 75,000/ mm(3)

• hemoglobin > 9 g/dL

• total bilirubin < 1.5 mg/dl

• creatinine <= 1.5 mg/dl

EXCLUSION CRITERIA:

Exclusion Criteria- All Cohorts

• Subjects who are receiving any other investigational agents.

• Subjects who have previously received rIL-12

• Subjects with active autoimmune diseases, that might deteriorate when receiving an immunostimulatory agent with the exceptions:

• diabetes type I, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible;

• subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses <= 10 mg of prednisone or equivalent per day;

• administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is eligible.

• History of organ transplant, except for transplants that do not require immunosuppression.

• History of or active inflammatory bowel disease (e.g., Crohn s disease, ulcerative colitis).

• Known hypersensitivity or allergic reactions attributed to any compounds of similar chemical or biologic composition to the study medication, such as recombinant IL-12 or other monoclonal antibodies and history of allergic reactions attributed to compounds of similar chemical composition to FUDR or heparin.

• Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke < 6 months prior to enrollment, myocardial infarction < 6 months prior to enrollment, unstable angina, congestive heart failure (>= NYHA III) or serious cardiac arrhythmia requiring medication.

• All conditions associated with significant necrosis of nontumor-bearing tissues.

• Esophageal or gastroduodenal ulcers < 6 months prior to treatment.

• Psychiatric illness/social situations that would limit compliance with study requirements.

• Active concurrent malignancies within the last five years other than colorectal primary except basal cell skin carcinoma and thyroid carcinoma.

• Prior radiation to liver.

• Subjects with active Hepatitis B or C infection.

• Significant acute or chronic infections (i.e., tuberculosis) history of exposure or history of positive tuberculosis test; plus, presence of clinical symptoms, physical or radiographic findings).

• Any condition, including the presence of laboratory abnormalities and/or insufficient normal liver parenchyma, which places the subject at unacceptable risk if they were to participate in the study or confounds the ability to interpret data from the study.

Exclusion Criteria-Metastatic Colorectal Carcinoma

-Subjects with incontrovertible radiographic evidence of disease outside of the colon/rectum (primary) and liver given unlikelihood of benefit from liver-directed therapy.

Note: Lung lesions seen on CT do not always represent metastases. They are very hard to qualify, therefore exception to this exclusion is subjects with fewer than five lung lesions greater than 1 cm that have not increased in size by more than 10% over a 4-month period of time and are amenable to resection should subsequent problematic growth occur. Lesions less than 1 cm are indeterminant as far as etiology is concerned and will be ignored. Subjects with liver metastases and oligometastatic lung lesions (we define oligometastatic as less than 5 amenable to thoracoscopic removal) are still likely to benefit from liver directed therapy.

• Subjects who have undergone extra-hepatic metastasectomy and have a documented disease-free interval less than or equal to 4 months.

• MSI-high subjects who need to be treated with check-point inhibitors.

• Prior treatment with FUDR.