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7.4.2 safety monitoring committee (smc)

This protocol will protocol will be periodically reviewed by an intramural Safety Monitoring Committee (SMC). Initial review will occur as soon as possible after the annual NIH Intramural IRB continuing review date. Subsequently, each protocol will be reviewed every 6 months as the quarterly meeting schedule permits or more frequently as may be required by the SMC based on the risks presented in the study. For initial and subsequent reviews, protocols will not be reviewed if there is no accrual within the review period.  
The SMC review will focus on unexpected protocol-specific safety issues that are identified during the conduct of the clinical trial. Written outcome letters will be generated in response to the monitoring activities and submitted to the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.
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7.4.3 independent monitoring committee (imc)

The protocol will also have an Independent Monitoring Committee (IMC), consisting of the Principal Investigator and two independent, qualified investigators who are outside of the Laboratory of Molecular Biology (LMB) branch and are not involved in the study. The committee will meet after the first 5 subjects have been treated and completed the DLT evaluation window. The IMC will review adverse events and other associated safety data (this review may occur prior to the first annual continuing review date). The committee will be responsible for deciding whether treatment can proceed under the current protocol, whether protocol modifications are required for study continuation, or whether the protocol should be closed to further accrual due to toxicity of the study agents. The IMC may be convened for an ad hoc evaluation of protocol safety by the Principal Investigator or at the request of the IRB or SMC at other occasions during the study if concerns about study drug or research protocol safety or toxicity arise. The minutes of the IMC meetings will be submitted to the IRB at the time of continuing review, unless an issue arises that requires prompt reporting to the IRB and then results will be submitted more expeditiously.
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8 sponsor safety reporting 8.1

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (ICH E6 (R2).
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8.1.2 serious adverse event (sae)

An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following:
- Death,
- A life-threatening adverse event (see Section **8.1.3**)  
- Inpatient hospitalization or prolongation of existing hospitalization o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery arranged prior to the start of the study), a planned hospitalization for pre-existing condition, or a procedure required by the protocol, without a serious deterioration in health, is not considered a serious adverse event.  
o A hospitalization/admission that is solely driven by non-medical reasons (e.g.,
hospitalization for patient convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to the hospital would not be considered a serious adverse event. The reason for seeking medical care should be evaluated for meeting one of the other serious criteria.  
- Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
- A congenital anomaly/birth defect.
- Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
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8.1.3 life-threatening

An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death. (21CFR312.32).
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8.1.4 severity

The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.
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8.1.5 relationship to study product

All AEs will have their relationship to study product assessed using the terms: related or not related.  
- Related - There is a reasonable possibility that the study product caused the adverse event. Reasonable possibility means that there is evidence to suggest a causal relationship between the study product and the adverse event.  
- Not Related - There is not a reasonable possibility that the administration of the study product caused the event.
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8.2 assessment of safety events

AE information collected will include event description, date of onset, assessment of severity and relationship to study product and alternate etiology (if not related to study product), date of resolution of the event, seriousness and outcome. The assessment of severity and relationship to the study product will be done only by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs occurring during the collection and reporting period will be documented appropriately regardless of relationship. AEs will be followed through resolution.  
SAEs will be:  
- Assessed for severity and relationship to study product and alternate etiology (if not related to study product) by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  
- Recorded on the appropriate SAE report form, the medical record and captured in the clinical database.  
- Followed through resolution by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to Section **6.1.** All serious adverse events recorded from the time of first investigational product administration must be reported to the sponsor.
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8.3 reporting of serious adverse

Any AE that meets a protocol-defined serious criteria or meets the definition of Adverse Event of Special Interest that require expedited reporting must be submitted immediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE report form.  
All SAE reporting must include the elements described in Section 8.2.  
SAE reports will be submitted to the Center for Cancer Research (CCR) at: OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and instructions can be found at: https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842 Following the assessment of the SAE by OSRO, other supporting documentation of the event may be requested by the OSRO Safety and should be provided as soon as possible.
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8.4 reporting pregnancy 8.4.1 maternal

If a patient becomes pregnant during the course of the study, the study treatment should be discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later than 24 hours of when the outcome of the Pregnancy become known, Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects and spontaneous miscarriages that meet serious criteria (see Section **8.1.2**) should be reported as SAEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up and documented.
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8.4.2 paternal exposure

Male patients should refrain from fathering a child or donating sperm during the study and for 3 months after the last dose of study drugs.  
Pregnancy of the patient's partner is not considered to be an AE. However, the outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date of the first dose until 3 months after the last dose should, if possible, be followed up and documented.
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8.5 regulatory reporting for studies

Following notification from the investigator, CCR, the IND sponsor, will report any suspected adverse reaction that is both serious and unexpected in expedited manner to the FDA in accordance to 21 CFR 31.2.32. CCR will report an AE as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the study product and the adverse event. CCR will notify FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety report of potential serious risks from clinical trials or any other source, as soon as possible, in accordance to 21 CFR Part 312.32. All serious events will be reported to the FDA at least annually in a summary format.
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9 clinical monitoring

As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring program. The CCR's program allows for confirmation of study data, specifically data that could affect the interpretation of primary and secondary study endpoints; adherence to the protocol, regulations, ICH E6, and SOPs; and human subjects protection. This is done through independent verification of study data with source documentation focusing on:  
- Informed consent process
- Eligibility confirmation
- Drug administration and accountability
- Adverse events monitoring - Response assessment.
The monitoring program also extends to multi-site research when the CCR is the coordinating center. This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified by training and experience to monitor the progress of clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial conduct.
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10 statistical considerations 10.1 statistical

The primary endpoint of the dose escalation phase is to identify the MTD and the desirable dose of LMB-100 with tofacitinib. The primary endpoint of the expansion phase is to determine the number of participants that meet a threshold serum drug concentration during cycle 2 of treatment. The threshold drug level has been set at >600 ng/mL as measured at EOI for any LMB-100 administration during the cycle of interest.
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10.1.2 secondary endpoints

The secondary endpoints for both the dose expansion and dose escalation cohorts are the LMB100 peak serum level, half-life and AUC during cycle 1, and the percentage of participants with EOI LMB-100 serum drug concentration that meets threshold during cycle 3. For the dose escalation cohort, the percentage of participants with EOI LMB-100 serum drug concentration that meets threshold during cycle 2 of treatment will also be measured. For the dose expansion cohort, the number and description of adverse events by grade will also be reported.
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10.2 sample size determination

The primary endpoints of this trial are to 1) identify the MTD and the desirable dose of the tofacitinib + LMB-100 combination format and 2) to determine whether the combination results in 80% of patients achieving threshold drug levels during cycle 2 of LMB-100. The MTD is defined as the maximum dose at which less than 33% of patients experience a DLT. The desirable dose will be selected from among the dose levels at or below the MTD. A lower dose than the MTD might be assessed in the expansion phase if chronic toxicity of LMB-100 is judged to be intolerable by the investigator at the MTD. As per standard 3+3 design, if 0 of 3 or <2 of 6 patients experience DLT then dose escalation may proceed. If 2 or more patients experience DLT at any dose level, then dose de-escalation is required. Dose escalation will proceed from dose level 1 to 2. If 0 of 3 or 0-1 of the first 6 patients in dose level 1 have a DLT, then dose escalation will proceed to dose level 2. Alternatively, if 2 or more patients in level 1 experience DLT, then dose will be de-escalated to dose level -1. Based on two dose levels, the theoretical maximum number of subjects that can enroll on the dose escalation would be 12 (6 patients per level x2 dose levels). Following completion of the dose escalation, enrollment of an additional 15 patients with pancreatic cancer or extrahepatic cholangiocarcinoma will be undertaken to better assess the a) safety of the optimal dose in the target population, and b) ability of tofacitinib to delay development of ADAs against LMB-100 and result in serum LMB-100 drug levels reaching threshold in cycle 2 and beyond. Participants on the dose escalation arm who are treated at MTD and meet eligibility requirements for the dose expansion phase can be counted towards the 15 patients needed to accrue to the expansion phase. We estimate that as many as 50% of patients who start treatment will develop progressive disease by restaging after 2 cycles and would therefore be uninformative for assessing the longer-term immunogenicity endpoint. Thus, additional patients may be needed to complete the evaluation of toxicity and possible efficacy at the escalating dose levels. This evaluation in 15 patients of either histology (but at least 8 patients in this expansion phase must have pancreatic adenocarcinoma) will be undertaken using the following guidelines: The objective will be to determine if the fraction of patients who are able to achieve threshold levels of LMB-100 in cycle 2 is consistent with 80% and greater than 50%. If 15 evaluable patients are enrolled, and if 11 or more patients meet threshold drug levels in cycle 2, then the probability of this occurring is 5.9% if the true probability of achieving threshold drug levels in cycle 2 were 50% and the probability of this occurring is 83.6% if the true probability of achieving threshold drug levels in cycle 2 were 80%. Thus, the expansion phase would be considered to have a positive outcome if 11 or more of 15 patients in the expansion phase achieve threshold drug levels. In practice, after the trial has ended accrual, the fraction of evaluable patients assessed during the expansion phase that achieve threshold drug levels in cycle 2 will be determined and reported along with two-sided 80% and 95% confidence intervals to aid in interpretation of the results. The fraction of patients who achieve threshold drug levels in cycle 3 will also be reported along with a 95% confidence interval, but this may be a small fraction and will be interpreted as being an exploratory evaluation. As an early stopping rule, if after the first 5 evaluable patients in the expansion cohort have been treated, 0 of the 5 achieve threshold drug levels in cycle 2, then no further patients will be accrued as soon as that can be determined, with no pause in accrual, since this would be inconsistent with the goal of having 11 or more of 15 patients achieving threshold drug levels in cycle 2. With up to 12 patients in the dose escalation phase and 15 in the expansion cohort, a maximum of 27 evaluable patients are required to complete accrual to this study. The accrual ceiling will be set at 45 patients to account for screen failures or patients who are treated but unable to complete the DLT period. It is anticipated that up to two patients per month may enroll onto this trial. Thus, accrual is expected be completed in approximately 2 years.
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10.3 populations for analyses 10.3.1

All patients who receive treatment during dose escalation will be reported. Any patient who receives any study drug treatment and experiences a DLT related to study drug within 21 days of initial treatment is evaluable. Otherwise, patients evaluable for DLT must: 1) receive all doses of study drugs, 2) be followed for study drug toxicity for at least 21 days after the administration of the first dose of LMB-100. In the expansion phase, up to 15 evaluable patients who can have their drug levels assessed in cycle 2 will be included in analyses. Up to 5 patients will be replaced if they have PD before C2, but if more than 5 patients progress before C2, then no further patients will be accrued as soon as this can be determined.
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10.3.2 evaluable for objective response

Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response.  
These patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Responses or progressions noted in patients receiving treatment extension will be recorded in the study database but will not be reported in the aggregate objective response rate, which only corresponds to assessments taken prior to the start of a 4th cycle.
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10.3.3 evaluable non-target disease response

Patients who have lesions or tumor marker present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions or increase in tumor marker.
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10.4 statistical analyses 10.4.1 general

The DLTs among patients enrolled during the dose escalation phase will be determined and reported at each dose level. In the expansion phase, the fraction of evaluable patients who have achieved threshold drug levels in cycle 2 will be reported.
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10.4.2 analysis of the primary

The DLTs among patients enrolled during the dose escalation phase will be determined and reported at each dose level. In the expansion phase, the fraction of evaluable patients who meet the endpoint drug level threshold in cycle 2 will be reported along with two-sided 80% and 95% confidence intervals to aid in interpretation of the results.
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10.4.3 analysis of the secondary

The secondary endpoints are the number and description of adverse events by grade in the expansion cohort. For both dose escalation and expansion cohorts secondary endpoints include: the LMB-100 peak serum level and half-life and AUC during cycle 1. Each of these will be reported using descriptive measures such as percentages and counts as appropriate. For both dose escalation and dose expansion cohorts, we will report the percentage of patients who have formation of neutralizing anti-LMB-100 ADAs affecting drug concentration during cycle 2 and cycle 3.
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10.4.4 safety analyses

Safety will be evaluated during the dose escalation phase and will include reporting toxicities by grade and type at each dose level in addition to DLTs. During the 15-patient expansion cohort, the following rule will be used: Within the initial 6 patients, no more than 1 patient in 6 is permitted to experience a DLT attributable to study agents. After the initial 6 patients, safety will be monitored continuously per the following rule: if the cumulative fraction of patients enrolled who experience a DLT attributable to study agents is 1/6 or less, patients will be allowed to continue to enroll onto this protocol.
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10.4.6 planned interim analyses

As an early stopping rule, if after the first 5 evaluable patients have been treated, 0 of the 5 meet threshold drug levels in cycle 2, then no further patients will be accrued since this is inconsistent with the goal of having 11 or more of 15 meeting threshold drug levels. Accrual will not be halted while awaiting the determination of drug levels in cycle 2 based on 5 patients; thus, additional patients may begin treatment while this determination is being made.
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10.4.7 sub-group analyses

In the expansion cohort, the fraction of patients meeting threshold drug levels in cycle 2 will be analyzed as an exploratory endpoint according to pancreatic adenocarcinoma vs. extra-hepatic cholangiocarcinoma history.
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10.4.9 exploratory analyses

The following are the intended exploratory analyses focusing on the patients in the expansion cohort: Disease control rate (DCR) at 9 weeks will be estimated along with a 95% confidence interval. PFS and OS will be estimated by the Kaplan-Meier method, along with 95% confidence intervals. Changes in appropriate tumor markers with treatment (if applicable to patient's tumor type) will be determined and tested for change from baseline using a Wilcoxon signed rank test. Titer of free anti-LMB-100 antibodies at the start of each cycle and following completion of treatment will be obtained and results reported descriptively; the relationship of these values with peak serum drug levels of LMB-100 will be explored. Association of response with tumor MSLN expression will be done by comparing levels between responders and non-responders using an appropriate nonparametric test such as a Cochran-Armitage test or Fisher's exact test. Changes in circulating endothelial cells following immunotoxin treatment, changes in serum cytokines following immunotoxin treatment, and changes in tumor microenvironment following immunotoxin treatment will be reported descriptively, with statistical testing of changes as appropriate. Any statistical tests performed on the exploratory endpoints will have results presented without formal adjustment but interpreted in the context of the number of tests performed. In patients receiving treatment extension, the anti-drug antibodies and peak plasma LMB-100 drug levels will be obtained at each cycle after cycle 3 and reported with descriptive statistics. The levels of these measures after cycle 3 may be compared descriptively to those in earlier cycles for purposes of evaluating the effect of the agent in this small subset of patients.
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11 human subjects protections 11.1

LMB-100 targets the cell surface antigen MSLN and is ineffective against tumor or normal cells that lack MSLN. Many different solid tumor types express MSLN such as mesothelioma, pancreatic, colorectal and lung adenocarcinomas, epithelial ovarian cancers, cholangiocarcinomas, gastric and triple negative breast cancers, as well as some tumors of squamous cell origin. At advanced stages, these tumors are incurable although standard therapies can improve duration of survival and symptoms. There is an unmet need to identify improved and less toxic therapies in these patient populations. Given the overall poor prognosis of these patients, particularly after progression of tumor on or after initial treatment regimen(s), the potential to directly benefit from treatment outweighs the risks of participating in the study.  
All patients meeting the criteria listed in Section 2.1 are eligible for enrollment.
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11.2 participation of children

There are no dosing or adverse event data currently available on the use of LMB-100 with tofacitinib in patients <18 years of age; therefore, children are excluded from this study.
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11.3 participation of subjects unable

Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation, all subjects ≥ age 18 will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an independent assessment of whether an individual has the capacity to provide consent; assistance in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint a surrogate. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 14E for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
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11.4 evaluation of benefits and

Patient safety will be managed by careful proactive patient selection prior to study to exclude patients at risk from study treatment due to their pre-existing conditions. During the study, safety of patients will be proactively managed by protocol-mandated physical examinations, vital signs assessments, chest X-rays, ECGs, clinical laboratory assessments, and collection of adverse events and their assessment.  
The risks of the study include those associated with study agent as discussed in Section 12.  
11.4.1.2 Blood Collection Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 11.4.1.3 Image Guided Biopsy Collection The risks of the research biopsies collected at screening, at cycle 1 day 1, and on day 3 of cycle 2 include pain, bleeding and infection at the biopsy site. 11.4.1.4 Risks of exposure to ionizing radiation This research involves up to 6 CT C/A/P scans, up to 3 chest X-ray, and up to 3 CT-guide biopsies per year. Subjects will be exposed to up to approximately 9.18 rem. This level of exposure is associated with an increased risk of cancer.
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11.4.1.5 mr imaging

MRI is a standard of care test for some patients with pancreatic and cholangiocarcinoma. The risks of MR imaging are relatively small. The US Food and Drug Administration has issued warnings that administration of gadolinium (updated September 9, 2010), the MRI contrast imaging agent used in this protocol, has been associated with development of a disease called **nephrogenic systemic fibrosis (NSF)**. The syndrome is rare (approximately 600 cases reported worldwide as of September 2010, out of several million administrations of gadolinium), but disabling and in some cases, fatal. All cases to date have occurred in patients with severe renal disease, including patients on dialysis. NSF has been nearly eradicated secondary to careful screening of renal function and avoiding use of gadolinium in patients with eGFR <30 ml/min/1.73 BSA. Even in patients with end stage renal disease, there have been only rare occurrences of NSF because of precautions taken to use more stable contrast agents at lower doses. This protocol excludes patients with renal insufficiency (eGFR <50 ml/min). The FDA has issued warnings in 2017 and 2018 that some gadolinium may be retained in the brain, bone and skin although health risks of accumulation have not been reported to date. In accordance with the FDA Drug Safety Communication of 05/16/2018, the Medication Guide for gadobutrol (or other macrocyclic gadolinium contrast agent if applicable) will be made available to all subjects with scans that will involve gadolinium-based contrast agent administration.
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11.4.1.6 central line insertion

Patients without a mediport in whom peripheral access cannot be obtained can have a central line placed for treatment administration. The risks of this procedure include catheter contamination, pneumothorax, arrhythmia and air embolus. All care will be taken to minimize complications of central insertion during the procedure.
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11.4.2 benefits

Patients with many different solid tumor types expressing MSLN are in continuous need of improved therapy options, particularly patients with pancreatic and biliary adenocarcinomas, the focus population of this clinical trial. Preclinical data has demonstrated promising anti-tumor efficacy of LMB-100 in xenograft models in monotherapy and combination therapy. Laboratory studies have demonstrated that tofacitinib inhibits the development of antibodies against LMB100. Therefore, LMB-100 + tofacitinib may improve clinical outcome of patients with mesothelinexpressing tumors. Several clinically appropriate strategies to minimize risk to patients have been built into the protocol through the means of inclusion/exclusion criteria, monitoring strategies, and management guidelines.
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11.5 consent process and documentation

The informed consent document will be provided to the participant or consent designee(s) (e.g., legally authorized representative [LAR] if participant is an adult unable to consent) for review prior to consenting. A designated study investigator will carefully explain the procedures and tests involved in this study, and the associated risks, discomforts and benefits. In order to minimize potential coercion, as much time as is needed to review the document will be given, including an opportunity to discuss it with friends, family members and/or other advisors, and to ask questions of any designated study investigator. A signed informed consent document will be obtained prior to entry onto the study. The initial consent process as well as re-consent, when required, may take place in person or remotely (e.g., via telephone or other NIH approved remote platforms) per discretion of the designated study investigator and with the agreement of the participant/consent designee(s). Whether in person or remote, the privacy of the subject will be maintained. Consenting investigators (and participant/consent designee, when in person) will be located in a private area (e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee will be informed of the private nature of the discussion and will be encouraged to relocate to a more private setting if needed.
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12 pharmaceutical and investigational device

LMB-100 was transferred to the NIH CC Pharmacy by Selecta Biosciences, the drug manufacturer. For this trial, the drug will be supplied by the NIH CC Pharmacy.
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12.1.1.1 mechanism of action

LMB-100 is a novel recombinant anti-mesothelin targeted cytolytic fusion protein (cFP) developed for the treatment of patients with solid tumors that express the mesothelin protein. Mesothelin is a suitable candidate for targeted therapy due to its very limited expression in normal/non-malignant tissue and its high expression in several tumor entities including mesothelioma, ovarian cancer, pancreatic cancer, gastric cancer, breast cancer, and lung cancer. To target mesothelin, a humanized Fab fragment of the anti-mesothelin antibody SS1 is linked to a truncated and de-immunized recombinant 24 kD fragment of Pseudomonas exotoxin (PE24). After binding to mesothelin, the complex isinternalized by endocytosis and kills cells by inhibition of eukaryotic elongation factor 2 (eEF2), leading to arrest of protein synthesis and secondarily triggering cell death by apoptosis or necrosis. 12.1.1.2 Molecular Weight: approximately 73 kDa  
 12.1.1.3 Chemical Structure
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12.1.2 toxicity

Information in thissection is based on preclinical studies with LMB-100, and clinical studies of the cytolytic fusion protein SS1-P. Participants should receive a full dose of LMB-100 unless a DLT and/or a treatment limiting toxicity is observed. In case of DLT and/or treatment limiting toxicities, treatment with LMB-100 will be stopped until resolution of toxicity to NCI CTCAE Grade  2 hematological toxicities or Grade  1 non-hematological toxicities. A delay of LMB-100 administration for up to two weeks of the planned schedule will be acceptable to allow for resolution of toxicity to NCI CTCAE Grade  2 hematological toxicities or Grade  1 nonhematological toxicities. If toxicity does not resolve to NCI CTCAE Grade  2 hematological toxicities or Grade  1 non-hematological toxicities and the participant is unable to resume treatment with LMB-100 after this time, no additional doses will be administered, and the participant will be withdrawn from study treatment. 12.1.2.1 Infusion-Related Reactions and Hypersensitivity Including Anaphylaxis LMB-100 administration may cause infusion-associated symptoms such as fever, chills, hypotension, shortness of breath, skin rash, headache, nausea, and/or vomiting. Such reactions typically occur during or shortly after an infusion. Participants may also develop IgE-mediated hypersensitivity reactions to LMB-100. IRRs may be indistinguishable from an anaphylactic reaction. Participants should receive full supportive care to treat IRRs or anaphylaxis according to institutional practice. If infusion-associated signs or symptoms occur, participants should be monitored until complete resolution. In vitro data and previous clinical experience with LMB-100 suggest that the risk for the release of pro-inflammatory cytokines upon first administration of LMB-100 to humans is low (Please refer to Sections **1.2.8** and **3.3.1** for details). Past experience with monoclonal antibodies that demonstrated a risk in the whole blood assay has shown that this risk could be effectively managed in the clinic with appropriate risk-minimization measures. The release of pro-inflammatory cytokines is believed to be partially responsible for the occurrence of IRRs.
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12.1.2.2 risk of immunogenicity and

LMB-100 may cause the formation of ADAs. These may trigger hypersensitivity reactions or immune complex-mediated responses. The development of ADAs to LMB-100, an improved cytolytic fusion protein with a humanized targeting moiety directed against mesothelin and a dehumanized, truncated Pseudomonas exotoxin A is expected to be less likely than SS1P. Clinical trials with SS1P have led to the development of neutralizing ADAs in 75% and 88% of participants after 1 cycle of therapy, in the IV bolus and continuous infusion trials respectively.(20) Participants will be monitored at regular intervals for the development of ADAs and cytokines. In particular, any clinical signs and symptoms suggestive of a hypersensitivity reaction and/or an immune complex-mediated reaction possibly due to ADA formation will be carefully investigated. 12.1.2.3 Risk of Inflammatory Reactions to Serosal Membranes LMB-100 administration may cause inflammatory reactions to serosal membranes including pleuritis, characterized by pleuritic chest pain, dyspnea, and hypoxia and pericarditis, characterized by precordial chest pain, congestive heart failure, hypotension, and uremia. Clinical trials with SS1P monotherapy have led to reversible pleuritis and pericarditis. Participants who develop symptoms of serosal inflammation should be closely monitored and receive standard treatments which may include corticosteroids. 12.1.2.4 Risk of Capillary Leak Syndrome LMB-100 administration may cause VLS characterized by hypotension, hypoalbuminemia, edema, weight gain, and hemoconcentration. Clinical trials with SS1P monotherapy have led to the development of reversible VLS. Participants will be monitored with frequent assessments of chest x-rays, weight, edema, blood pressure, and serum albumin levels prior to and during treatment.  
Participants who develop symptoms of VLS should be closely monitored and receive standard symptomatic treatments.
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12.1.2.5 risk of renal toxicity

LMB-100 administration may cause renal toxicity characterized by increased creatinine, BUN, and proteinuria. In preclinical cynomolgus monkey studies, LMB-100 has shown increases in creatinine and histological changes including regenerative and degenerative changes to the tubular epithelium. Hemolytic uremic syndrome has been reported for other cytolytic fusion antibodies in development. Participantsshould be monitored with renal laboratory assessmentsincluding creatinine, BUN, and urinalysis.
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12.1.2.6 risk of cardiac toxicity

There may be a risk for cardiac immune-related adverse events, specifically **myocarditis**, as a rare but serious complication after treatment with LMB-100. During clinical trial 19C0128, a patient with history of intrahepatic cholangiocarcinoma arising out of primary sclerosing cholangitis, initiated C1 tofacitinib + apixaban treatment on Day 1 and LMB-100 on Day 4. The patient began experiencing fatigue and pleuritic pain symptoms on Day 5. A cardiac MRI was performed that suggested a component of inflammatory myocarditis in addition to capillary leak syndrome 12.1.2.7 Injection Site Reactions LMB-100 administration may cause adverse reactions at the infusion site characterized by pain, swelling, induration, and nodules. In preclinical NHP studies for both SS1P and LMB-100 reddening and swelling of the infusion site were noted. Participants who develop symptoms of infusion site reactions can be administered pain relieving medication (analgesic) as required, and rotation of infusion sites is recommended.
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12.1.2.8 pregnancy

No studies assessing the reproductive and developmental toxicity of LMB-100 have been conducted to date. It is not known whether LMB-100 can cross the placenta or cause harm to the fetus when administered to pregnant women or whether it affects reproductive capacity. LMB-100 should not be administered to pregnant women.
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12.1.3 formulation and preparation

LMB-100 drug product (20 mg/20 mL) is provided for syringe infusion as a sterile, colorless to brownish, preservative-free liquid in single-use, 20 mL vials. The nominal fill volume is 20 mL and the approximate concentration of LMB-100 recombinant fusion protein in the vialsis 1 mg/mL.
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12.1.4 stability and storage

Chemical and physical in-use stability for undiluted LMB-100 drug product in syringes has been demonstrated for 24 hours at 2-8 °C and 24 hours at ambient temperature.
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12.1.6 incompatibilities

Pharmacodynamic drug interaction studies have not been conducted. LMB-100 is contraindicated in subjects with a history of severe allergic anaphylactic reactions to humanized, chimeric or mouse peptides/antibodies or to any components of the product.
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12.2 tofacitinib

Please refer to the FDA-approved package insert for product information, and a comprehensive list of adverse events. Version Date: *08/19/20*
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12.2.1 source

Tofacitinib is commercially available in 5 and 10 mg tablets. Immediate release formulation will be used for this protocol.
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13 references

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4. Zhang, Y., Hochster, H., Stein, S., and Lacy, J. (2015) Gemcitabine plus nab-paclitaxel for advanced pancreatic cancer after first-line FOLFIRINOX: single institution retrospective review of efficacy and toxicity. *Experimental hematology & oncology* 4, 29
5. Portal, A., Pernot, S., Tougeron, D., Arbaud, C., Bidault, A. T., de la Fouchardiere, C.,
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Murawa, P., Walde, D., Wolff, R. A., Campos, D., Lim, R., Ding, K., Clark, G., Voskoglou-Nomikos, T., Ptasynski, M., Parulekar, W., and National Cancer Institute of Canada Clinical Trials, G. (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. *Journal of clinical oncology : official journal of* the American Society of Clinical Oncology 25, 1960-1966 7. Rahma, O. E., Duffy, A., Liewehr, D. J., Steinberg, S. M., and Greten, T. F. (2013) Secondline treatment in advanced pancreatic cancer: a comprehensive analysis of published clinical trials. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 24, 1972-1979 8. Valle, J., Wasan, H., Palmer, D. H., Cunningham, D., Anthoney, A., Maraveyas, A.,
Madhusudan, S., Iveson, T., Hughes, S., Pereira, S. P., Roughton, M., Bridgewater, J., and Investigators, A. B. C. T. (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. *The New England journal of medicine* 362, 1273-1281 9. Hassan, R., Thomas, A., Alewine, C., Le, D. T., Jaffee, E. M., and Pastan, I. (2016)
Mesothelin Immunotherapy for Cancer: Ready for Prime Time? *Journal of clinical* oncology : official journal of the American Society of Clinical Oncology 34, 4171-4179 10. Cheng, W. F., Huang, C. Y., Chang, M. C., Hu, Y. H., Chiang, Y. C., Chen, Y. L., Hsieh, C. Y., and Chen, C. A. (2009) High mesothelin correlates with chemoresistance and poor survival in epithelial ovarian carcinoma. *British journal of cancer* 100, 1144-1153 11. Wang, L., Niu, Z., Zhang, L., Liu, X., Wang, X., Li, F., and Wang, Y. (2012)
Clinicopathological significance of mesothelin expression in invasive breast cancer. *The* Journal *of international medical research* 40, 909-916  
12. Thomas, A., Chen, Y., Steinberg, S. M., Luo, J., Pack, S., Raffeld, M., Abdullaev, Z.,
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mutations and a poor prognosis. *Oncotarget* 6, 11694-11703 13. Nomura, R., Fujii, H., Abe, M., Sugo, H., Ishizaki, Y., Kawasaki, S., and Hino, O. (2013)
Mesothelin expression is a prognostic factor in cholangiocellular carcinoma. International surgery 98, 164-169
14. Winter, J. M., Tang, L. H., Klimstra, D. S., Brennan, M. F., Brody, J. R., Rocha, F. G., Jia, X., Qin, L. X., D'Angelica, M. I., DeMatteo, R. P., Fong, Y., Jarnagin, W. R., O'Reilly, E. M., and Allen, P. J. (2012) A novel survival-based tissue microarray of pancreatic cancer validates MUC1 and mesothelin as biomarkers. *PloS one* 7, e40157  
15. Li, M., Bharadwaj, U., Zhang, R., Zhang, S., Mu, H., Fisher, W. E., Brunicardi, F. C.,
Chen, C., and Yao, Q. (2008) Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer. *Molecular cancer therapeutics* 7, 286-296 16. Uehara, N., Matsuoka, Y., and Tsubura, A. (2008) Mesothelin promotes anchorageindependent growth and prevents anoikis via extracellular signal-regulated kinase signaling pathway in human breast cancer cells. *Molecular cancer research : MCR* 6, 186193
17. Servais, E. L., Colovos, C., Rodriguez, L., Bograd, A. J., Nitadori, J., Sima, C., Rusch, V.  
W., Sadelain, M., and Adusumilli, P. S. (2012) Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients. Clinical cancer research : an official journal of the American Association for Cancer Research 18, 2478-2489  
18. Chen, S. H., Hung, W. C., Wang, P., Paul, C., and Konstantopoulos, K. (2013) Mesothelin binding to CA125/MUC16 promotes pancreatic cancer cell motility and invasion via MMP-7 activation. *Scientific reports* 3, 1870
19. Weldon, J. E., and Pastan, I. (2011) A guide to taming a toxin--recombinant immunotoxins constructed from Pseudomonas exotoxin A for the treatment of cancer. *The FEBS journal* 278, 4683-4700 20. Hassan, R., Bullock, S., Premkumar, A., Kreitman, R. J., Kindler, H., Willingham, M. C.,
and Pastan, I. (2007) Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 13, 5144-5149 21. Hassan, R., Miller, A. C., Sharon, E., Thomas, A., Reynolds, J. C., Ling, A., Kreitman, R.  
J., Miettinen, M. M., Steinberg, S. M., Fowler, D. H., and Pastan, I. (2013) Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression. *Science translational medicine* 5, 208ra147  
22. Hollevoet, K., Mason-Osann, E., Liu, X. F., Imhof-Jung, S., Niederfellner, G., and Pastan, I. (2014) In Vitro and In Vivo Activity of the Low-Immunogenic Antimesothelin Immunotoxin RG7787 in Pancreatic Cancer. *Molecular cancer therapeutics* 13, 2040-2049 23. Alewine, C., Xiang, L., Yamori, T., Niederfellner, G., Bosslet, K., and Pastan, I. (2014)
Efficacy of RG7787, a next-generation mesothelin-targeted immunotoxin, against triplenegative breast and gastric cancers. *Molecular cancer therapeutics* 13, 2653-2661 24. Bauss, F., Lechmann, M., Krippendorff, B. F., Staack, R., Herting, F., Festag, M., ImhofJung, S., Hesse, F., Pompiati, M., Kollmorgen, G., da Silva Mateus Seidl, R., Bossenmaier, B., Lau, W., Schantz, C., Stracke, J. O., Brinkmann, U., Onda, M., Pastan, I., Bosslet, K., and Niederfellner, G. (2016) Characterization of a re-engineered, mesothelin-targeted Pseudomonas exotoxin fusion protein for lung cancer therapy. *Mol Oncol* 25. Zhang, J., Khanna, S., Jiang, Q., Alewine, C., Miettinen, M., Pastan, I., and Hassan, R.  
(2016) Efficacy of Anti-Mesothelin Immunotoxin RG7787 plus nab-Paclitaxel against Mesothelioma Patient Derived Xenografts and Mesothelin as a Biomarker of Tumor Response. *Clinical cancer research : an official journal of the American Association for* Cancer Research 26. Weldon, J. E., Xiang, L., Zhang, J., Beers, R., Walker, D. A., Onda, M., Hassan, R., and Pastan, I. (2013) A Recombinant Immunotoxin against the Tumor-Associated Antigen Mesothelin Reengineered for High Activity, Low Off-Target Toxicity, and Reduced Antigenicity. *Molecular cancer therapeutics* 12, 48-57 27. Liu, W., Onda, M., Lee, B., Kreitman, R. J., Hassan, R., Xiang, L., and Pastan, I. (2012)
Recombinant immunotoxin engineered for low immunogenicity and antigenicity by identifying and silencing human B-cell epitopes. Proceedings of the National Academy of Sciences of the United States of America 109, 11782-11787 28. Fleischmann, R., Kremer, J., Cush, J., Schulze-Koops, H., Connell, C. A., Bradley, J. D.,
Gruben, D., Wallenstein, G. V., Zwillich, S. H., Kanik, K. S., and Investigators, O. S. (2012) Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. *The New* England journal of medicine 367, 495-507 29. Sandborn, W. J., Su, C., Sands, B. E., D'Haens, G. R., Vermeire, S., Schreiber, S., Danese, S., Feagan, B. G., Reinisch, W., Niezychowski, W., Friedman, G., Lawendy, N., Yu, D., Woodworth, D., Mukherjee, A., Zhang, H., Healey, P., Panes, J., Octave Induction, O. I., and Investigators, O. S. (2017) Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. The New England *journal of medicine* 376, 1723-1736 30. Villarino, A. V., Kanno, Y., Ferdinand, J. R., and O'Shea, J. J. (2015) Mechanisms of Jak/STAT signaling in immunity and disease. *Journal of immunology* 194, 21-27 31. Quintas-Cardama, A., and Verstovsek, S. (2013) Molecular pathways: Jak/STAT pathway:
mutations, inhibitors, and resistance. *Clinical cancer research : an official journal of the* American Association for Cancer Research 19, 1933-1940 32. Onda, M., Ghoreschi, K., Steward-Tharp, S., Thomas, C., O'Shea, J. J., Pastan, I. H., and FitzGerald, D. J. (2014) Tofacitinib suppresses antibody responses to protein therapeutics in murine hosts. *Journal of immunology* 193, 48-55 33. Desai, R. J., Pawar, A., Weinblatt, M. E., and Kim, S. C. (2019) Comparative Risk of Venous Thromboembolism in Rheumatoid Arthritis Patients Receiving Tofacitinib Versus Those Receiving Tumor Necrosis Factor Inhibitors: An Observational Cohort Study.  
Arthritis & rheumatology (Hoboken, N.J.) 71, 892-900 34. Farge, D., Frere, C., Connors, J. M., Ay, C., Khorana, A. A., Munoz, A., Brenner, B.,
Kakkar, A., Rafii, H., Solymoss, S., Brilhante, D., Monreal, M., Bounameaux, H., Pabinger, I., and Douketis, J. (2019) 2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. The Lancet. Oncology 35. Key, N. S., Khorana, A. A., Kuderer, N. M., Bohlke, K., Lee, A. Y. Y., Arcelus, J. I.,
Wong, S. L., Balaban, E. P., Flowers, C. R., Francis, C. W., Gates, L. E., Kakkar, A. K., Levine, M. N., Liebman, H. A., Tempero, M. A., Lyman, G. H., and Falanga, A. (2019) Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. *Journal of clinical oncology : official journal of the* American Society of Clinical Oncology, Jco1901461 36. Siegall, C. B., Liggitt, D., Chace, D., Mixan, B., Sugai, J., Davidson, T., and Steinitz, M.  
(1997) Characterization of vascular leak syndrome induced by the toxin component of Pseudomonas exotoxin-based immunotoxins and its potential inhibition with nonsteroidal anti-inflammatory drugs. *Clinical cancer research : an official journal of the American* Association for Cancer Research 3, 339-345 37. Kuan, C. T., Pai, L. H., and Pastan, I. (1995) Immunotoxins containing Pseudomonas exotoxin that target LeY damage human endothelial cells in an antibody-specific mode: relevance to vascular leak syndrome. Clinical cancer research : an official journal of the American Association for Cancer Research 1, 1589-1594 38. Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R.,
Dancey, J., Arbuck, S., Gwyther, S., Mooney, M., Rubinstein, L., Shankar, L., Dodd, L., Kaplan, R., Lacombe, D., and Verweij, J. (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). *European journal of cancer* 45, 228-247 39. Byrne, M. J., and Nowak, A. K. (2004) Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 15, 257-260
40. Scher, H. I., Halabi, S., Tannock, I., Morris, M., Sternberg, C. N., Carducci, M. A.,
Eisenberger, M. A., Higano, C., Bubley, G. J., Dreicer, R., Petrylak, D., Kantoff, P., Basch, E., Kelly, W. K., Figg, W. D., Small, E. J., Beer, T. M., Wilding, G., Martin, A., Hussain, M., and Prostate Cancer Clinical Trials Working, G. (2008) Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26, 1148-1159  
41. Rustin, G. J., Quinn, M., Thigpen, T., du Bois, A., Pujade-Lauraine, E., Jakobsen, A.,
Eisenhauer, E., Sagae, S., Greven, K., Vergote, I., Cervantes, A., and Vermorken, J. (2004) Re: New guidelines to evaluate the response to treatment in solid tumors (ovarian cancer).  
J Natl Cancer Inst 96, 487-488 42. Bubley, G. J., Carducci, M., Dahut, W., Dawson, N., Daliani, D., Eisenberger, M., Figg, W. D., Freidlin, B., Halabi, S., Hudes, G., Hussain, M., Kaplan, R., Myers, C., Oh, W., Petrylak, D. P., Reed, E., Roth, B., Sartor, O., Scher, H., Simons, J., Sinibaldi, V., Small, E. J., Smith, M. R., Trump, D. L., Wilding, G., and et al. (1999) Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 17, 3461-3467 43. Vergote, I., Rustin, G. J., Eisenhauer, E. A., Kristensen, G. B., Pujade-Lauraine, E.,
Parmar, M. K., Friedlander, M., Jakobsen, A., and Vermorken, J. B. (2000) Re: new guidelines to evaluate the response to treatment in solid tumors [ovarian cancer].  
Gynecologic Cancer Intergroup. *J Natl Cancer Inst* 92, 1534-1535
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14 appendices

| 14.1                                                                                                                                                            | APPENDIX A- PERFORMANCE STATUS CRITERIA ECOG Performance Status Scale   | Karnofsky Performance Scale                                                                                   |              |            |       |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------|--------------|------------|-------|
| Grade                                                                                                                                                           | Descriptions                                                            | Percent                                                                                                       | Description  |            |       |
| 100                                                                                                                                                             | Normal, no complaints, no evidence  of disease.                         |                                                                                                               |              |            |       |
| Normal activity. Fully active, able to                                                                                                                          |                                                                         |                                                                                                               |              |            |       |
| 0                                                                                                                                                               | carry on all pre-disease performance  without restriction.              | Able to carry on normal activity;                                                                             |              |            |       |
| 90                                                                                                                                                              | minor signs or symptoms of disease.                                     |                                                                                                               |              |            |       |
| Symptoms,                                                                                                                                                       | but                                                                     | ambulatory.                                                                                                   |              |            |       |
| Restricted in physically strenuous  activity, but ambulatory and able to  carry out work of a light or sedentary  nature (e.g., light housework, office  work). | 80                                                                      | Normal activity with effort; some  signs or symptoms of disease.                                              |              |            |       |
| 1                                                                                                                                                               | 70                                                                      | Cares for self, unable to carry on  normal activity or to do active work. Requires occasional assistance, but |              |            |       |
| 60                                                                                                                                                              | is able to care for most of his/her  needs.                             |                                                                                                               |              |            |       |
| In                                                                                                                                                              | bed                                                                     | <50%                                                                                                          | of           | the        | time. |
| Ambulatory and capable of all selfcare, but unable to carry out any work  activities. Up and about more than  50% of waking hours.                                                                                                                                                                 |                                                                         |                                                                                                               |              |            |       |
| 2                                                                                                                                                               | 50                                                                      | Requires                                                                                                      | considerable | assistance |       |
| and frequent medical care.                                                                                                                                      |                                                                         |                                                                                                               |              |            |       |
| 40                                                                                                                                                              | Disabled, requires special care and  assistance.                        |                                                                                                               |              |            |       |
| In bed >50% of the time. Capable of  only limited self-care, confined to  bed or chair more than 50% of  waking hours.                                          |                                                                         |                                                                                                               |              |            |       |
| 3                                                                                                                                                               | Severely disabled, hospitalization                                      |                                                                                                               |              |            |       |
| 30                                                                                                                                                              | indicated. Death not imminent.                                          |                                                                                                               |              |            |       |
| 20                                                                                                                                                              | Very sick, hospitalization indicated.  Death not imminent.              |                                                                                                               |              |            |       |
| 100%                                                                                                                                                            | bedridden.                                                              | Completely                                                                                                    |              |            |       |
| disabled. Cannot carry on any selfcare. Totally confined to bed or  chair.                                                                                                                                                                 |                                                                         |                                                                                                               |              |            |       |
| 4                                                                                                                                                               | 10                                                                      | Moribund,                                                                                                     | fatal        | processes  |       |
| progressing rapidly.                                                                                                                                            |                                                                         |                                                                                                               |              |            |       |
| 5                                                                                                                                                               | Dead.                                                                   | 0                                                                                                             | Dead.        |            |       |  
Version Date: *08/19/20*
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14.2 appendix b-model chemotherapy note

Bolded text should be replaced with patient-specific information.  
(1)
Tofacitinib, 10 mg PO bid, Days 1-10 (2)
LMB-100: <**dose per schema**> mcg/kg, IV on Days 4, 6, 8 given over 30 minutes
- Run with 1:10 in-line dilution of normal saline = **<mg LMB-100>** * 18 = **\# ml/hr**
LMB-100 dose for patients weighing more than 100 kg will be calculated as if they weigh 100kg.  
Pre-medications to be given 30-60 minutes prior to LMB-100 o Diphenhydramine 25-50 mg PO or IV
o Ranitidine 150 mg PO (see **Table 11** for alternative formulations)
o Acetaminophen 650 mg PO
Additional medications: -Dexamethasone 8 mg IV, PRN severe infusion related reaction (should be available on unit) -Ondansetron 8 mg PO q8h, PRN nausea Please encourage oral hydration of ~1.5 L daily while receiving LMB-100.  
89 Version Date: *08/19/20*
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14.3 appendix c- patient medication

| 14.3 APPENDIX C- PATIENT MEDICATION DIARY Cycle #_______ Patient Name________________________________ Patient Study ID _____________________________ INSTRUCTIONS TO THE PATIENT: 1. Complete one form for each Cycle. 2. You will take 1 pill of 10 mg tofacitinib in the morning and also 1 pill of 10 mg tofacitinib in the evening each day. Do  not crush or chew. 3. Record the date and what time you took them.  4. If you have any comments or notice any side effects, please record them in the Comments column. 5. Please bring your pill bottles and this form to your physician when you go for your next appointment. 6. If a dose is missed, log this in Comments column and call the Study Team for instructions on what to do. Do not take  additional doses to make up missed dose unless instructed to do so by the study team. Tofacitinib (taken twice a day) Date Day Time (AM) Time (PM) Comments (side effects or missed doses) 1 2 3 4   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
90 Version Date: *08/19/20*  
| 5 6 7 8 9 10                                                                                                                                                           |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Patient's Signature: ___________________________________ Date: ____________________ Staff Signature: _______________________________________Date: ____________________ |