First-line Treatment in Locally Advanced or Metastastic Small Bowel Adenocarcinoma

Background:

Small bowel adenocarcinoma (SBA) is rare malignant disease accounting for less than 5% of all gastrointestinal tumors [1]. At time of first diagnosis about 40% of patients have distant metastases and more than half of the patients with initially resected SBA and lymph node invasion will experience metastatic recurrence [2]. Tumor phenotype characterization indicates that SBA molecular alterations are similar to adenocarcinoma of the colorectum [3, 4].

Palliative chemotherapy in SBA was mainly evaluated within retrospective studies. Fluoropyrimidines in combination with platinum derivates, especially oxaliplatin, appear to be the most efficient treatment regimen [5, 6]. The median progression-free survival (PFS) ranges from 6.9 to 8.7 months. Two prospective phase II studies evaluated the efficacy of oxaliplatin in combination with 5-fluorouracil (5-FU) or the oral prodrug capecitabine reporting an objective response rate (ORR) of approximately 50% with a median PFS of 7.8 and 11.3 months, and a median overall survival (OS) of 15.2 and 20.4 months, respectively [7, 8]. Indeed, FOLFOX regimen (5-FU+ oxaliplatin) represents the standard of care chemotherapy used worldwide [9, 10]. Treatment with anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibody was evaluate in a pilot study that report no signal of efficacy [11]. The anti-Vascular Endothelial Growth Factor (VEGF) monoclonal antibody Bevacizumab was also evaluated in a phase II trial in combination with capecitabine and oxaliplatin [12] with comparable results observed in a previous phase II trial investigating the same chemotherapy regimen without bevacizumab [7, 8]. Moreover, a registry study suggests that there is no benefit of adding bevacizumab to chemotherapy in first-line treatment of SBA [13]. Thus, it seems that FOLFOX or CAPOX (capecitabine+ oxaliplatin) without the addition of a monoclonal antibody represents one of the best therapeutic options in first-line treatment of SBA.

In metastatic colorectal adenocarcinoma the triplet regimen consisting of 5-FU, folinic acid, oxaliplatin, and irinotecan demonstrated an improved efficacy compared to doublet regimen depending on molecular subtype [14]. The median PFS was better in patients receiving triplet regimen compared to doublet chemotherapy (9.8 months versus 6.9 months). Moreover, in metastatic pancreatic adenocarcinoma triplet chemotherapy with FOLFIRINOX represents the current standard of care due to a significantly improved PFS and OS compared to former standard treatment with gemcitabine [15].

In SBA, a phase II trial including a small number of patients evaluated the triplet chemotherapy with capecitabine, irinotecan, and oxaliplatin. The authors reported a moderate ORR of 37.5%, a median PFS of 8.9 months, and a median OS of 13.4 months [16]. The moderate efficacy might be a result of the unusual choice of capecitabine instead of infusional 5-FU as component of the triplet regimen.

The superiority of triplet chemotherapy in molecularly selected metastatic colorectal cancer and metastatic pancreatic adenocarcinoma advocate an evaluation in first-line setting of SBA.

The optimal sequence of currently available treatment regimens in SBA is under debate. There is small evidence for the use of irinotecan-based regimens, such as FOLFIRI [17], taxane-based regimens [18], or molecularly targeted therapy [19] in subsequent treatment lines.

In the past decades, little progress has been made in the treatment of SBA with regard to survival parameters [20] in contrast to other entities, such as mCRC. The lack of prospective clinical trials resulting in a lack of evidence-based treatment recommendations can be identified as one of the main reasons for missing improvements in the treatment of SBA.

Due to the rarity of SBA, it is not feasible to conduct a phase III study of adequate duration. Therefore, a randomized phase II study will be conducted to not only validate the efficacy signal of triplet chemotherapy with mFOLFIRINOX in the first-line treatment of SBA, but also to generate evidence for national therapy guidelines and to improve the medical care of patients with SBA.

Objectives:

Primary objective

• To compare the efficacy of doublet chemotherapy with FOLFOX and triplet chemotherapy with mFOLFIRINOX in first-line treatment of SBA Secondary objectives
• To compare efficacy, safety and patient patient-reported quality of life (QoL) of doublet chemotherapy with FOLFOX and triplet chemotherapy with mFOLFIRINOX in first-line treatment of SBA
• To assess efficacy of subsequent antitumor treatment Exploratory objectives
• To identify predictive and prognostic factors and to characterize patient subgroups in order to correlate their genetic and molecular tumor characteristics with clinical efficacy and toxicity using tumor specimen and blood-based biomarker candidates
• To identify the optimal sequence of antitumoral treatment in irresectable or metastatic SBA.

Endpoints:

Primary study endpoint Progression-free survival (PFS)-, defined as time from the date of randomization to the date of first radiological disease progression according to RECIST version 1.1 or the date of death from any cause.

Secondary study endpoints Efficacy

• Overall survival (OS)
• Objective response rate (ORR)
• Depth of response (DpR)

Safety

• Type, incidence, severity, and causal relationship to active chemotherapystudy treatment of non-serious adverse events and serious adverse events (severity evaluated according to CTCAE version 56.0) Quality of life
• Quality of life (QoL) as assessed with the QoL questionnaire EQ-5D-5L Exploratory endpoints
• Efficacy endpoints according to circulating tumor DNA (ctDNA) at baseline and at pre-defined time points during study treatment
• Effficacy endpoints according to molecular alterations
• Effficacy endpoints according to circulating tumor DNA (ctDNA)
• Treatments (including regimen, duration, efficacy) beyond study treatment
• PFS of subsequent treatment line (PFS2, 2nd line PFS)

Trial design:

This is an open-label, randomized, controlled, multicenter, phase II trial with two parallel arms. Patients with locally advanced irresectable or metastatic small bowel adenocarcinoma are randomized in a 1:1 fashion to investigate the efficacy, patient -reported quality of life and safety of triplet chemotherapy with mFOLFIRINOX (arm A) versus doublet chemotherapy with FOLFOX (arm B).

During the randomization process stratification will be performed according to the following parameters:

1. Locally advanced versus synchronous metastatic versus metachronous metastatic metastatic SBASBA 2. ECOG performance status 0-1 versus 2

Systemic treatment in both arms is performed biweekly until disease progression, occurence of unacceptable toxicity, at the patient's request, at discretion of the investigator, whatever occurs first.

Patients will be followed up with regard to disease progression, survival and if applicable subsequent treatments until death or for at least 4 years after randomization, whichever date occurs first.

Inclusion criteria:

Participants Patients are eligible to be included in the trial only if all of the following criteria apply at time of enrollment:

1. Patient's signed informed consent.
2. Patient's age ≥18 years at the time of signing the informed consent.
3. Histologically confirmed small bowel adenocarcinoma.
4. Microsatellite stable tumor or proficient mismatch repair status of the SBA (immunohistochemistry and polymerase chain reaction are both allowed for characterization)
5. Predicted locally advanced irresectable by the local study team or presenting with distant metastases.
6. Patient did not receive antitumor treatment for locally advanced irresetable or metastatic disease.
7. Measurable lesion according to RECIST 1.1.
8. ECOG performance status 0-2. In case of patient's age >70 years, ECOG has to be 0 or 1 at randomization
9. Adequate bone marrow, hepatic and renal organ function, defined by the following laboratory test results:

• Absolute neutrophil count 1.5 x 109/L (1500/µL)
• Hemoglobin ≥ 80 g/L (8 g/dL) with or without blood transfusion
• Platelet count ≥ 100 x109/L (100000/µL) without transfusion
• Total serum bilirubin of ≤ 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) ≤ 2.5 × ULN; if liver function abnormalities are due to underlying liver metastasis, AST and ALT ≤ 5 × ULN
• Aspartate aminotransferase (AST/GOT) ≤ 3.0 × ULN.
• Calculated glomerular filtration rate (GFR) according to Cockcroft-Gault formula or according to MDRD ≥ 50 mL/min or serum creatinine≤ 1.5x ULN

1. Patients without anticoagulation need to present with an INR< 1.5x ULN and aPTT <1.5x ULN. Patient with prophylactic or therapeutic anticoagulation are allowed into the trial.
2. Proficient fluorouracil metabolism as defined:

• Prior treatment with 5-FU or capecitabine without unusal toxicity or
• If tested, normal DPD deficiency test according to the standard of the study site or
• If tested, in patients with DPD deficiency test with a CPIC activity score of 1.0-1.5 fluoropyrimidine dosage should be reduced by 50%

1. For women of childbearing potential (WOCBP): negative pregnancy test within 14 days before randomization and agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of study treatment.

A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (≥12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male partner's sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

For men: Wwith female partners of childbearing potential,: men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 6 months after the last dose of study treatment. Men must refrain from donating sperm during this same period.

Men Wwith pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 6 months after the last dose of study medication to avoid exposing the embryo.

Exclusion criteria:

Patients are excluded from this trial if any of the following criteria apply at time of enrollment:

1. Adenocarcinoma of the ampulla of Vateri
2. Ileus or directly imminent ileus as assessed by the local study team. Patients with treated and resolved ileus are allowed into the trial.
3. Previous chemotherapy for metastatic or irresectable disease.
4. Adjuvant chemotherapy completed less than 6 months ago 4. New York Heart Association Class III or greater heart failure by clinical judgement.
5. Myocardial infarction within 6 months prior to randomization; percutaneous transluminal coronary angioplasty (PTCA) with or without stenting within 6 months prior to randomization.
6. Unstable angina pectoris. 7. Unstable cardiac arrhythmia >grade 2 NCI CTCAE despite anti-arrhythmic therapy.
7. Ongoing toxicities >grade 2 NCI CTCAE, in particular peripheral neuropathy. 9. Active uncontrolled infection by investigator's perspective. 10. Severe chronic non-healing wounds, ulcerous lesions or untreated bone fracture.
8. Known hypersensitivity to 5-FU, leucovorin, capecitabine, irinotecan or oxaliplatin or to any of the other excipients listed in section 6.1 of the corresponding SmPC.
9. Recent or concomitant treatment with brivudine. 13. Peripheral sensitive neuropathy with functional impairment (> grade 1 acc. to CTCAE version 65.0 (see appendix 2)).
10. Simultaneous application of Johannis herbs preparations. 15. Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency. 16. Major surgical procedure, open biopsy, or significant traumatic injury within 21 days prior to randomization that may interfere with systemic therapy as judged by the investigator.
11. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications.
12. Medical history of malignant disease other than small bowel adenocarcinomaSBA with the following exceptions: 18.1. patients who have been disease-free for at least three years before randomization 18.2. patients with adequately treated and completely resected basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer, stage I uterine cancer 18.3. patients with any treated or untreated malignant disease that is associated with a 5-year survival prognosis of ≥ 80% and does not require active therapy at randomization 18.4.18.3. 19. Known alcohol or drug abuse. 20. Pregnant or breastfeeding females. 21. Participation in a clinical trial or experimental drug treatment within 28 days prior to potential inclusion in the clinical trial or within a period of 5 half-lives of the substances administered in a clinical trial or during an experimental drug treatment prior to potential inclusion in the clinical trial, depending on which period is longest, or simultaneous participation in another clinical trial while taking part in this clinical trial.
13. Patients dependentd on Sponsor, investigator or study site. 23. Patient committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
14. Limited legal capacity. 25. Inability to undergo the medical follow-up of the trial for geographical, social or psychological reasons.

Treatment, dosage, and administration:

Treatment arm A: mFOLFIRINOX every two weeks

• oxaliplatin 85 mg/m² 2 hours intravenously
• irinotecan 150 mg/m² 60-90 minutes intravenously
• leucovorin 400 mg/m² 2 hours intravenously
• 5-fluorouracil 2400 mg/m² 46 hours continuous intravenous infusion Treatment arm B: FOLFOX every two weeks
• oxaliplatin 85 mg/m² 2 hours intravenously
• leucovorin 400 mg/m² 2 hours intravenously
• 5-fluorouracil 400 mg/m² intravenous bolus injection
• 5-fluorouracil 2400 mg/m² 46 hours continuous intravenous infusion

Dose de-escalations and dose modifications are allowed per institutional standard as investigators decision.

Systemic treatment in both arms will be continued until disease progression, occurence of unacceptable toxicity, at the patient's request, at discretion of the investigator, whatever occurs first.

Translational research:

The translational research program consists of the following steps but might be modified or expanded taking latest scientific data into account :

1. Characterization of tumor specimens for DNA mutations and RNA expressions (for example panel NGS and mRNA expression analysis)
2. Longitudinal assessments of tumor markers and circulating tumor DNA (according to initial tumor characteristics), assessments should include the baseline, 3 months, and 6 months time points (and optional further time points as long as no disease progression occurred as scheduled above).
3. Characterization of tumor specimen obtained after relapse of disease during or after study (if occurring and available) for DNA mutations and RNA expressions.

This paired sample collection including specimen and the longitudinal assessment of circulating tumor DNA will be performed in order to inform about early detection of disease progression (potentially prior to radiographic correlate), patterns of disease progression and molecular background of disease progression (tumor evolution, secondary mutations, expressions).

Statistical considerations:

With a power of 80%, a 2-sided alpha of 0,1, a total of 73 events are need to be observed in order to detect a difference in progression-free survival of a hazard ratio of 0.557- favoring the experimental treatment vs. control (Schoenfeld formula) in a 1:1 randomized trial, assuming a PFS 6.1 months for the control arm and 10.9 months for the experimental arm. Assuming an accrual time of 36 months and a follow-up time of 24 months for the primary endpoint, a drop-out/censoring rate of 10% after randomization , a total of 112 patients (56 per group) in the respective arms, rounded to receive integers and maintain the allocation ratio) is expected to yield the required number of events if the accrual rate is constant. From the available data mentioned above, it was assumed that the event rate follows an exponential distribution without reaching a relevant plateau. The computation was done using the software R Version 3.5.1 and the package Rpact.

PFS will be estimated by Kaplan-Meier-Curves and comparison of treatment arms will be performed by using a Cox-Regression with adjustment for the stratification factors (Locally advanced versus metastatic SBA; Synchronous versus metachronous metastases; ECOG performance status 0-1 versus 2), Hazard Ratio for the main factor treatment group with 90% Wald-Confidence intervals will be reported. Primary analysis will be performed on the FAS data set.

Duration and end of trial:

First patient in (FPI) to Last patient in (LPI): 36 months

Primary endpoint (PFS) after randomization: LPI+ 10 months (46 months total) Secondary endpoints: LPI+ 48 months (84 months total)

End of Study (EOS) Last visit of last patient (LVLP) Last patient in (LPI)+ 48 months (FPI+ 90 months in total)