M9241 in Combination With Hepatic Artery Infusion Pump (HAIP) and Systemic Therapy for Subjects With Metastatic Colorectal Cancer or Intrahepatic Cholangiocarcinoma

• ClinicalTrials.gov Identifier: NCT05286814
• Recruitment Status: Recruiting
• First Posted: March 18, 2022
• Last Update Posted: May 20, 2024
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information

• First Submitted Date: March 12, 2022
• First Posted Date: March 18, 2022
• Last Update Posted Date: May 20, 2024
• Actual Study Start Date: October 24, 2022
• Estimated Primary Completion Date: December 31, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 17, 2022)

Determine overall response rates [ Time Frame: baseline, every 8 weeks while on treatment, and 4-8 wkks following initial documentation of objective response ]

Simon optimal two-stage Phase II trial design will be used to determine overall response using RECIST criteria. The clinical response rate (CR+PR) will be determined and reported along with a 95% confidence interval, separately by cohort.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 13, 2024)

• Determine overall survival (OS) [ Time Frame: date of enrollment until death from any cause, or after 5 years off treatment ]
  CT will be used for response criteria. Overall survival (OS) probability will be determined using Kaplan-Meier estimates for all participants, separately by cohort; the median OS will be reported along with a 95% confidence interval.
• Determine extra-hepatic progression-free survival (PFS) [ Time Frame: date of operation to date of first observation of progressive disease within the liver or death, or after 5 years off treatment whichever comes first ]
  CT will be used for response criteria. Extra-hepatic progression-free survival (PFS) probability will be determined using Kaplan-Meier estimates for all participants, separately by cohort; the median PFS will be reported along with a 95% confidence interval.
• Evaluate safety of M9241 in combination with HAIP therapy [ Time Frame: on-going from treatment start through end of treatment visit ]
  Safety will be assessed by analyzing the type, grade and frequency. Toxicities by grade and per participant will be determined and reported separately by disease cohort.
• Determine hepatic progression-free survival (PFS) [ Time Frame: date of operation to date of first observation of progressive disease within the liver or death, or after 5 years off treatment whichever comes first ]
  CT will be used for response criteria. Hepatic progression-free survival (PFS) probability will be determined using Kaplan-Meier estimates for all participants, separately by cohort; the median PFS will be reported along with a 95% confidence interval.

Original Secondary Outcome Measures (submitted: March 17, 2022)

• Determine overall survival (OS) [ Time Frame: date of enrollment until death from any cause, or after 5 years off treatment ]
  CT will be used for response criteria. Overall survival (OS) probability will be determined using Kaplan-Meier estimates for all subjects, separately by cohort; the median OS will be reported along with a 95% confidence interval.
• Determine extra-hepatic progression-free survival (PFS) [ Time Frame: date of operation to date of first observation of progressive disease within the liver or death, or after 5 years off treatment whichever comes first ]
  CT will be used for response criteria. Extra-hepatic progression-free survival (PFS) probability will be determined using Kaplan-Meier estimates for all subjects, separately by cohort; the median PFS will be reported along with a 95% confidence interval.
• Evaluate safety of M9241 in combination with HAIP therapy [ Time Frame: on-going from treatment start through end of treatment visit ]
  Safety will be assessed by analyzing the type, grade and frequency. Toxicities by grade and per participant will be determined and reported separately by disease cohort.
• Determine hepatic progression-free survival (PFS) [ Time Frame: date of operation to date of first observation of progressive disease within the liver or death, or after 5 years off treatment whichever comes first ]
  CT will be used for response criteria. Hepatic progression-free survival (PFS) probability will be determined using Kaplan-Meier estimates for all subjects, separately by cohort; the median PFS will be reported along with a 95% confidence interval.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: M9241 in Combination With Hepatic Artery Infusion Pump (HAIP) and Systemic Therapy for Subjects With Metastatic Colorectal Cancer or Intrahepatic Cholangiocarcinoma
• Official Title: 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

Brief Summary

Background:

One way to treat liver cancer is to deliver chemotherapy drugs only to the liver (and not to the whole body). Researchers want to see if adding the drug M9241 can improve the treatment. The drug triggers the immune system to fight cancer.<TAB>

Objective:

To see if treatment with HAIPs to deliver liver-directed chemotherapy in combination with M9241 is effective for certain cancers.

Eligibility:

People aged 18 and older who have cancer of the bile ducts that is only in the liver, or colorectal cancer that has spread to the liver.

Design:

Participants will be screened with:

Medical history

Physical exam

Blood tests

Pregnancy test (if needed)

Tumor biopsy (if needed)

Electrocardiogram

Computed tomography (CT) scans

Participants will have an abdominal operation. A catheter will be placed into an artery that feeds blood to the liver. The catheter will then be attached to the HAIP. The HAIP will lay under the skin on the left side of the abdomen.

Participants will have chemotherapy drugs or heparin with saline infused into the HAIP every 2 weeks. M9241 will be injected under the skin every 4 weeks. They will get systemic chemotherapy through an IV or mediport every 2 weeks. They will receive this treatment until their cancer gets worse or they have bad side effects.

Participants will have 2 study visits each month. They will have CT scans every 8 weeks. At visits, they will repeat some screening tests.

Participants will have a follow-up visit 1 month after treatment ends. Then they will be contacted every 6 months for 5 years.

Detailed Description

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-y. IFN-y 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 participants with unresectable metastatic colorectal cancer (mCRC) and intrahepatic cholangiocarcinoma (ICC) treated with M9241 in combination with HAIP and systemic 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
• Participants must have received first-line systemic chemotherapy.
• Age >= 18 years

Design:

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

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Metastatic Colorectal Cancer (Mcrc)
• Intrahepatic Cholangiocarcinoma (Icc)
• Colorectal Cancer
• Colorectal Neoplasms
• Cholangiocarcinoma
• Intrahepatic Bile Duct Cancer
• Bile Duct Cancer
• Bile Duct Neoplasms

Intervention

• Drug: Floxuridine
  HAIP FUDR and Dexamethasone treatment on D1 of every cycle. Floxuridine: (0.12 mg/kg x ideal average body weight in kg X 30 mL [pump volume] / Pump Flow Rate)
• Drug: 5-Fluorouracil
  IV systemic chemotherapy on D1 and D15 of every cycle, beginning C2D1; treatment assigned by Arm. Arm 1: will receive either FOLFOX (leucovorin, 5-FU and oxaliplatin) or FOLFIRI (leucovorin, 5-FU and irinotecan). FOLFOX: oxaliplatin (85 mg/m2) and leucovorin (400 mg/m2) IV infusion administered concurrently via Y-Line over 120 minutes, then a 46-hour infusion of 5FU (2000 mg/m2) administered via an ambulatory device on site. FOLFIRI: irinotecan (150 mg/m2) and leucovorin (400 mg/m2) IV infusion administered concurrently via Y-Line over 30 minutes, then a 46-hour infusion of 5FU (2000 mg/m2) administered via an ambulatory device on site.
• Drug: Irinotecan
  IV systemic chemotherapy on D1 and D15 of every cycle, beginning C2D1; treatment assigned by Arm. Arm 1: will receive either FOLFOX (leucovorin, 5-FU and oxaliplatin) or FOLFIRI (leucovorin, 5-FU and irinotecan); FOLFIRI: irinotecan (150 mg/m2) and leucovorin (400 mg/m2) administered concurrently via Y-Line over 30 minutes, then a 46-hour infusion of 5-FU (2000 mg/m2) administered via an ambulatory device on site.
• Device: Intera 3000 Hepatic Artery Infusion Pump (HAIP)
  Intera 3000 HAIP will be filled with mixture of Floxuridine and Dexamethasone in 25,000 units heparin/saline (Heparin + 0.9% Sodium Chloride) on Day 1; Days 1-14 of every cycle pump will perfuse drugs to liver. On Day 15 of each cycle, the pump will be emptied and filled with 30,000 units heparin/saline (Heparin + 0.9% Sodium Chloride); Days 15-28 of every cycle will perfuse heparin/saline to liver.
• Drug: Oxaliplatin
  IV systemic chemotherapy on D1 and D15 of every cycle, beginning C2D1; treatment assigned by Arm. Arm 1: either FOLFOX (leucovorin, 5-FU and oxaliplatin) or FOLFIRI (leucovorin, 5-FU and irinotecan); FOLFOX: oxaliplatin (85 mg/m2) and leucovorin (400 mg/m2) administered concurrently via Y-Line over 120 minutes, then a 46-hour infusion of 5-FU (2000 mg/m2) administered via an ambulatory device on site. Arm 2: GemOx (gemcitabine [800 mg/m2 IV over 30 minutes] and oxaliplatin [85 mg/ m2 IV over 120 minutes])
• Drug: Leucovorin
  IV systemic chemotherapy on D1 and D15 of every cycle, beginning C2D1; treatment assigned by Arm. Arm 1: will receive either FOLFOX (leucovorin, 5-FU and oxaliplatin) or FOLFIRI (leucovorin, 5-FU and irinotecan); FOLFOX: oxaliplatin (85 mg/m2) and leucovorin (400 mg/m2) administered concurrently via Y-Line over 120 minutes, then a 46-hour infusion of 5-FU (2000 mg/m2) administered via an ambulatory device on site. FOLFIRI: irinotecan (150 mg/m2) and leucovorin (400 mg/m2) administered concurrently via Y-Line over 30 minutes, then a 46-hour infusion of 5-FU (2000 mg/m2) administered via an ambulatory device on site.
• Drug: M9241
  M9241 will be administered by subcutaneous injection on Day 15 of every cycle. Cycle 1 at 12 mcg/kg; Cycle 2 reduced to 8 mcg/kg with the addition of systemic chemotherapy, to continue for further cycles. Note: any dose reduction in FUDR = 50% due to liver enzyme elevations means that the dose of M9241 will be reduced to 4 mcg/kg.
• Drug: Gemcitabine
  IV systemic chemotherapy on D1 and D15 of every cycle, beginning C2D1; treatment assigned by Arm. Arm 2: GemOx (gemcitabine [800 mg/m2 IV over 30 minutes] and oxaliplatin [85 mg/ m2 IV over 120 minutes])
• Drug: Dexamethasone
  HAIP FUDR and Dexamethasone treatment on D1 of every cycle. Dexamethasone: (1 mg/day X pump volume / pump flow rate)

Study Arms

• Experimental: 1/ HAIP +M9241+FOLFOX or FOLFORI
  M9241+HAIP FUDR and Dexamethasone chemotherapy in combination with FOLFOX or FOLFIRI
  Interventions:

  • Drug: Floxuridine
  • Drug: 5-Fluorouracil
  • Drug: Irinotecan
  • Device: Intera 3000 Hepatic Artery Infusion Pump (HAIP)
  • Drug: Oxaliplatin
  • Drug: Leucovorin
  • Drug: M9241
  • Drug: Dexamethasone
• Experimental: 2/HAIP +M9241+GemOx
  M9241+HAIP FUDR and Dexamethasone chemotherapy in combination with GemOx
  Interventions:

  • Drug: Floxuridine
  • Drug: 5-Fluorouracil
  • Drug: Irinotecan
  • Device: Intera 3000 Hepatic Artery Infusion Pump (HAIP)
  • Drug: Oxaliplatin
  • Drug: Leucovorin
  • Drug: M9241
  • Drug: Gemcitabine
  • Drug: Dexamethasone

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 17, 2022): 48
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2028
• Estimated Primary Completion Date: December 31, 2027 (Final data collection date for primary outcome measure)

Eligibility 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 participants is required unless the female partner is permanently sterile.
• Breastfeeding participant must agree to discontinue breastfeeding.
• Arterial anatomy on CT angiogram or CT chest, abdomen and pelvis multiphase (i.e., CT C/A/P multiphase) amenable to placement of the HAIP.
• Participant must sign the informed consent form to participate in this study.
• HIV-positive participants may be considered for this study only if they have an undetectable viral load.
• Participants 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 .
• Participant s liver metastases must not be amenable to resection/ablation to No Evidence of Disease (NED) in one stage.
• Participant must be able to tolerate systemic chemotherapy at initiation of study treatment as outlined below (mCRC: FOLFOX or FOLFIRI; ICC: GemOx or FOLFOX).

Inclusion Criteria-Metastatic Colorectal Carcinoma

• Participants must have histologically or cytologically confirmed diagnosis of colorectal adenocarcinoma metastatic to the liver (Cohort 1).
• Participants must have measurable liver metastatic disease.
• Participants must have received 1st line systemic chemotherapy.
• ECOG performance status <= 1.

• Participants 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 > 8 g/dL
  • total bilirubin < 1.5 X institutional upper limit of normal
  • AST(SGOT)/ALT(SGPT) < 2.5 X institutional upper limit of normal
  • creatinine within normal institutional limits OR eGFR within normal as predicted by the CKD-EPI equation > 60 mL/min/1.73 m2.

Inclusion Criteria-Intrahepatic Cholangiocarcinoma

• Participants must have histologically or cytologically confirmed diagnosis of intrahepatic cholangiocarcinoma confined to the liver (Cohort 2). 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.
• Participants must have radiographically measurable disease
• Disease must be considered unresectable at the time of preoperative evaluation.
• Participants must have received 1st line systemic chemotherapy
• ECOG performance status <= 1.

• Participants 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 > 8 g/dL
  • total bilirubin < 1.5 mg/dl
  • creatinine <= 1.5 mg/dl

EXCLUSION CRITERIA:

Exclusion Criteria- All Cohorts

• Participants who are receiving any other investigational agents.
• Participants who have previously received rIL-12.
• Participants 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;
• Participants 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.
• Active ischemic bowel disease.
• 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.
• Participants 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 participant 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

-Participants 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 participants 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. Participants 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.

• Participants who have undergone extra-hepatic metastasectomy and have a documented disease-free interval less than or equal to 4 months.
• MSI-high participants who need to be treated with check-point inhibitors.
• Prior treatment with FUDR.

Exclusion Criteria-Intrahepatic Cholangiocarcinoma

-Presence of distant metastatic disease. Clinical or radiographic evidence of metastatic disease to regional lymph nodes will be allowed, provided it is amenable to resection.

Note: Lung lesions seen on CT do not always represent metastases. They are very hard to qualify, therefore exception to this exclusion is participants 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 indeterminate as far as etiology is concerned and will be ignored. Participants 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.

• Prior treatment with FUDR.
• Diagnosis of sclerosing cholangitis.
• Clinical evidence or portal hypertension (ascites, gastroesophageal varices, or portal vein thrombosis).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Cathleen E Hannah, C.R.N.P.; (240) 858-7006; cathleen.hannah@nih.gov

Contact: Jonathan M Hernandez, M.D.; (240) 760-6072; jonathan.hernandez@nih.gov

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05286814
• Other Study ID Numbers: 10000307; 000307-C
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request.@@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: Clinical data available during the study and indefinitely.@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data are made available via dbGaP through requests to the data custodians.

• Current Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
• Original Responsible Party: Same as current
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Jonathan M Hernandez, M.D.; National Cancer Institute (NCI)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: May 14, 2024