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8.1 reporting period

For serious adverse events, the active reporting period begins from the time that the subject provides signed informed consent, which is obtained prior to the subject's participation in the study, ie, prior to undergoing any study-related procedure and/or receiving investigational product, through and including 28 calendar days after the last administration of the investigational product or including 60 calendar days after the last administration of the investigational product if no other therapy is administered. Should an investigator be made aware of any serious adverse event occurring any time after the active reporting period, it must be promptly reported. Adverse events (serious and non-serious) should be recorded on the CRF from the time the subject has taken at least one dose of study treatment through last subject visit. If a subject begins a new anticancer therapy, the adverse event reporting period for non-serious adverse events ends at the time the new treatment is started. Death must be reported if it occurs during the serious adverse event reporting period after the last dose of investigational product, irrespective of any intervening treatment.
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8.2 definition of an adverse

An adverse event is any untoward medical occurrence in a clinical investigation subject administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. Examples of adverse events include but are not limited to:  
Abnormal test findings; Clinically significant symptoms and signs; Changes in physical examination findings; Hypersensitivity/allergy; Drug abuse; Drug dependency.
Additionally, they may include the signs or symptoms resulting from:
Drug overdose; Drug withdrawal;  
Drug misuse; Drug interactions; Extravasations; Exposure during pregnancy;
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exposure via breastfeeding medication error.

Worsening of signs and symptoms of the malignancy under study should be reported as adverse events in the appropriate section of the CRF. Disease progression assessed by measurement of malignant lesions on radiographs or other methods should not be reported as adverse events.
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8.3 abnormal test findings

The criteria for determining whether an abnormal objective test finding should be reported as an adverse event are as follows:
Test result is associated with accompanying symptoms; and/or  
Test result requires additional diagnostic testing or medical/surgical intervention; and/or Test result leads to a change in study dosing (outside of protocol-stipulated dose adjustments) or discontinuation from the study, significant additional concomitant drug treatment, or other therapy; and/or Test result is considered to be an adverse event by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not constitute an adverse event. Any abnormal test result that is determined to be an error does not require reporting as an adverse event. 8.4 Serious Adverse Events A serious adverse event is any untoward medical occurrence at any dose that:
Results in death; Is life-threatening (immediate risk of death);
Requires in-patient hospitalization or prolongation of existing hospitalization;  
Results in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions);
Results in congenital anomaly/birth defect;
Progression of the malignancy under study (including signs and symptoms of progression) should not be reported as a serious adverse event unless the outcome is fatal within the safety reporting period. Hospitalization due to signs and symptoms of disease progression should not be reported as serious adverse event. If the malignancy has a fatal outcome during the study or within the safety reporting period, then the event leading to death must be recorded as an adverse event and as a serious adverse event with CTCAE Grade 5. Medical and scientific judgment is exercised in determining whether an event is an important medical event. An important medical event may not be immediately life-threatening and/or result in death or hospitalization. However, if it is determined that the event may jeopardize the subject or may require intervention to prevent one of the other adverse event outcomes, the important medical event should be reported as serious. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of drug dependency or drug abuse.
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8.5 causality assessment

The investigator's assessment of causality must be provided for all adverse events (serious and non-serious); the investigator must record the causal relationship in the CRF, as appropriate, and report such an assessment in accordance with the serious adverse reporting requirements if applicable. An investigator's causality assessment is the determination of whether there exists a reasonable possibility that the investigational product caused or contributed to an adverse event; generally the facts (evidence) or arguments to suggest a causal relationship should be provided. If the investigator does not know whether or not the investigational product caused the event, then the event will be handled as "related to investigational product" for reporting purposes. If the investigator's causality assessment is
"unknown but not related to investigational product", this should be clearly documented on study records. In addition, if the investigator determines a serious adverse event is associated with study procedures, the investigator must record this causal relationship in the source documents and CRF, as appropriate, and report such an assessment in accordance with the serious adverse event reporting requirements.
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8.6 risks associated with trastuzumab

Trastuzumab is a recombinant monoclonal antibody that binds specifically and with high affinity to the extracellular domain of HER2. Trastuzumab has been shown to inhibit the proliferation of human tumor cells overexpressing HER2 both in *vitro* and in *vivo*. The clinical benefit of trastuzumab in women with MBC has been demonstrated in two pivotal studies. A phase 2 trial (H0649g) assessed the activity of single-agent trastuzumab in 222 women with HER2-overexpressing MBC with progressive disease after one or more chemotherapy regimens (Cobleigh, et al, 1999). An independent response evaluation committee identified 8 complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval [CI]: 11% to 21%). The median duration of response was 9.1 months, and the median duration of survival was 13 months. The most common adverse events, which occurred in approximately 40% of subjects, were mild to moderate infusion-associated fever and/or chills. The most clinically significant event was cardiac dysfunction, which occurred in 4.7% of subjects. An open-label, randomized, phase 3 study (H0648g) in 469 subjects with HER2-positive MBC was conducted to evaluate the efficacy of trastuzumab in combination with chemotherapy as first-line treatment. Subjects who were anthracycline-naïve were randomized to receive either anthracycline plus cyclophosphamide (AC) or trastuzumab plus AC. Subjects who had received prior anthracyclines in the adjuvant setting were randomized to receive either paclitaxel or trastuzumab plus paclitaxel. As determined by an independent response evaluation committee, trastuzumab prolonged median time to disease progression from 4.6 months to 7.4 months (p < 0.001), improved the overall response rate (complete and partial responses) from 32% to 50% (p < 0.001), and increased median duration of response from 6.1 to 9.1 months (p < 0.001). Compared to chemotherapy alone, the addition of trastuzumab significantly lowered the incidence of death at one year from 33% to 22% (p = 0.008) and increased median overall survival 24% from 20.3 months to 25.1 months (p = 0.046) (Slamon, et al, 2001). The observed survival advantage remained despite crossover of 66% of subjects initially randomized to chemotherapy alone who elected to receive trastuzumab upon disease progression (Tripathy, et al, 2000). Fever/chills were observed with the initial trastuzumab infusion in approximately 25% of subjects. Class III or IV cardiac dysfunction was observed in 16% of the trastuzumab + AC subgroup; increasing age was an associated risk factor for the development of cardiotoxicity in this treatment cohort (Slamon, et al, 2001). Based on these data, trastuzumab was approved by the US Food and Drug Administration (FDA) for use in HER2-overexpressing MBC in combination with paclitaxel for first-line treatment and as a single agent for patients failing prior chemotherapy for metastatic disease. Trastuzumab is also currently approved in the early breast cancer setting. See the trastuzumab (Herceptin®) prescribing information for additional information.
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8.7 risks associated with ado-trastuzumab

The following summarizes the experience with ado-trastuzumab emtansine in multiple breast cancer studies to date. The usual dose used in the studies was 3.6 mg/kg every 3 weeks. Trastuzumab emtansine has demonstrated a favorable toxicity and tolerability profile to date across multiple studies. In a phase 1, TDM3569g, trastuzumab emtansine was administered every 3 weeks. The MTD of trastuzumab emtansine administered every 3 weeks was 3.6 mg/kg. DLTs consisted of Grade 3 and 4 thrombocytopenia that prevented retreatment in 2 of 3 subjects treated at 4.8 mg/kg on the every-3-week schedule. Grade ≥ 2 adverse events at the MTD were infrequent and manageable. The most common adverse events (≥ 25% incidence) seen in this study were thrombocytopenia, fatigue, nausea, anemia, constipation, headache, increased liver function tests, and cough. Every-3-week trastuzumab emtansine schedules are well tolerated and associated with significant clinical activity. In addition, the phase 2 studies, TDM4258g and TDM4374g, have shown similar tolerability of trastuzumab emtansine at a dose of 3.6 mg/kg administered every 3 weeks. Reversible thrombocytopenia has been commonly observed in completed and ongoing studies with trastuzumab emtansine. Most events were Grade 1 or 2; with Grade 3 or 4 thrombocytopenia has been observed less commonly. The incidence of Grade 1 thrombocytopenia gradually increased over successive cycles; however, there was no increase in the proportion of Grade 3 abnormalities. The number of subjects who experienced platelet count recovery to normal levels by Day 1 of the subsequent cycle decreased with successive cycles, suggesting a modest cumulative effect of trastuzumab emtansine on platelet count. There was no clear association between thrombocytopenia and *severe* hemorrhagic events; however, the use of platelet transfusions has been reported. Transient and reversible increases in serum AST and ALT have been observed across the trastuzumab emtansine studies. Grade 1 and 2 events have been observed frequently; Grade 3 to 4 events have been observed much less commonly. The incidence of increased AST was substantially higher than that for ALT. Increases in AST and ALT were commonly observed by Day 8 of each cycle and generally returned to baseline by Day 21. The proportion of subjects with Grade 1 and 2 increases in transaminases increased with successive cycles; however, no increase in the proportion of Grade 3 abnormalities over time was observed. To date, there have been no cases meeting Hy's Law criteria for drug-induced liver injury caused by trastuzumab emtansine. Although significant hepatotoxicity has rarely been seen in clinical trials with trastuzumab emtansine to date, the relationship to trastuzumab emtansine has not been established. Nevertheless, severe liver injury remains an important potential risk.  
Infusion-related reactions are known to occur with the administration of monoclonal antibodies and have been reported with trastuzumab emtansine. Infusion reaction adverse events occurred rarely and were mostly Grade 1 or 2. Non-specific symptoms that occurred on the first day of trastuzumab emtansine infusion that could be associated with an infusion reaction included fatigue; nausea; chills; pyrexia; and less commonly, headache; hypertension; vomiting; and cough. Pneumonitis has been rarely reported with trastuzumab emtansine. Signs, symptoms, and clinical findings include dyspnea, cough, fatigue, and pulmonary infiltrates. There were no fatalities among the cases of pneumonitis reported with trastuzumab emtansine. In clinical trials with trastuzumab emtansine, peripheral neuropathy has been reported, mainly as Grade 1 toxicity. Hypokalemia and decreases in serum potassium have been reported in completed and ongoing studies with trastuzumab emtansine. Most of these adverse events were Grade 1 or 2. Although significant cardiac events have been infrequent in clinical trials with trastuzumab emtansine to date, severe cardiotoxicity remains an important potential risk. Treatment with trastuzumab, a component of trastuzumab emtansine, has resulted in subclinical and clinical cardiac failure manifesting as CHF, decreased LVEF, and cardiac death. The incidence and severity of cardiac dysfunction was highest in subjects who received trastuzumab concurrently with anthracycline-containing chemotherapy regimens. Cardiotoxicity, manifesting as a decline in left ventricular ejection fraction (LVEF) or congestive heart failure (CHF), is being closely monitored in the current study. Rare cases of Grade 3 cardiac dysrhythmias have been reported among subjects receiving trastuzumab emtansine, although a direct relationship to study drug remains unclear. Given the potential for trastuzumab emtansine, and trastuzumab to cause cardiac toxicity, only subjects without significant cardiac history, with acceptable anthracycline exposure, and with an LVEF determined to be ≥ 50% by screening ECHO or MUGA scan are eligible for participation in this study. Repeat ECHO or MUGA scans will be performed at baseline and the beginning of Cycle 5 and then every 4 cycles thereafter, using the same noninvasive monitoring technique each time, to determine if therapy should be held or discontinued in asymptomatic subjects on the basis of local assessment of declines in LVEF. Any subject with symptomatic cardiac dysfunction or a significant decline in LVEF as detected by noninvasive cardiac imaging will discontinue all study treatment but will continue to be followed for 30 days for adverse events and serious adverse events and every 6 weeks for disease progression until the initiation of another anti-cancer therapy, subject- or investigator-initiated withdrawal from the study, or study termination.
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8.8 infusion-related symptoms with hypersensitivity

Infusion-related reactions consisting of fever and/or chills have been observed in ≤ 40% of patients during their first infusions of either trastuzumab or ado-trastuzumab emtansine. The symptoms have usually been mild to moderate and controlled with acetaminophen, diphenhydramine, or meperidine. These symptoms are uncommon with subsequent infusions. However, in the post-approval setting, more severe adverse reactions to trastuzumab have been reported. These have been categorized as hypersensitivity reactions (including anaphylaxis), infusion reactions, and pulmonary events. In rare cases, the reaction culminated in a fatal outcome. Administration of ado-trastuzumab emtansine, trastuzumab and utomilumab will be performed in a setting with emergency equipment and staff who are trained to monitor and respond to medical emergencies. Subjects will be monitored during each study medication infusion, for 60 minutes after the first infusion, and for 30 minutes after subsequent infusions in the absence of infusion-related adverse events. If infusion-associated symptoms occur, the subject will be monitored until symptoms completely resolve or are considered by the investigator to be clinically insignificant. Subjects who experience infusion-related symptoms during the administration of ado-trastuzumab emtansine, trastuzumab or utomilumab may be pre-medicated for subsequent infusions. Subjects who experience a Grade ≥ 3 allergic reaction or acute respiratory distress syndrome will discontinue all study treatment but will continue to be followed for 30 days for adverse events and serious adverse events and every 6 weeks for disease progression until the initiation of another anti-cancer therapy, subject- or investigator-initiated withdrawal from the study, or the study termination.
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8.9 rationale for continued dosing

Subjects who meet the criteria for ongoing clinical benefit will be allowed to continue study treatment in the absence of disease progression, unacceptable toxicity, or the initiation of other anti-cancer therapy, unless the study is terminated early for one of the reasons described in Sections 4.8 and 11.
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9. correlative/special studies 9.1 biomarkers

Serum and intratumoral biomarkers linked to immunomodulation and cytokine release, exploratory PD biomarkers expressed by PBMC and intratumoral lymphocytes, markers of T- and NK-cell phenotype, quantitation of T-cell receptor sequences, and tumor biopsy for analysis of exploratory mechanistic biomarkers such as IHC assessment of tumor-infiltrating lymphocytes and quantitation of T-cell receptor sequences will be collected as indicated in the Schedule of Activity (Appendix 3). A more detailed accounting of the biomarker collection/analysis is provided in Appendix 5.
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10. regulatory considerations

Throughout this document, reference to the "Sponsor-investigator" includes designates. Sponsor-investigator retains all defined responsibilities of the IND-holder, unless specifically delegated or transferred.
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10.1 institutional review of protocol

The protocol, the proposed informed consent and all forms of participant information related to the study (eg, advertisements used to recruit participants) will be reviewed and approved by the Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC). The Protocol Director will disseminate the protocol amendment information to all participating investigators. One version of the protocol document should be used at all times. Prior to implementation, the Stanford IRB and SRC will prospectively approve of any amendment to the protocol, except where necessary to eliminate an immediate hazard(s) to trial subjects. With the exception of actions to protect the safety and welfare of human subjects, any changes to the protocol will be submitted as a modification to the IRBs of record for the clinical site, and will be approved by the IRB of record prior to implementation.
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10.4 subject registration

Subjects may be registered to participate in this study when they have confirmed to meet all eligibility requirements (see Eligibility Criteria in Section 3 Participant Selection), and that eligibility has been reviewed (Eligibility Triple-check, see Eligibility Checklist in Appendix 6). All study participants will be entered into OnCore.
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10.5 data and safety monitoring

The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the monitoring entity for this study. The DSMC will audit study-related activities approximately once per year to determine whether the study has been conducted in accordance with the protocol; local standard operating procedures; FDA regulations; and Good Clinical Practice (GCP). This may include review of the following types of documents: regulatory binders, case report forms, eligibility checklists, and source documents. In addition, the DSMC will regularly review serious adverse events and protocol deviations to ensure the protection of human subjects. Results of the DSMC audit will be communicated to the IRB and the appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as needed.
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10.6 data management plan

The Principal Investigator, or his/her designee, will prepare and maintain adequate and accurate participant case histories with observations and data pertinent to the study. Study-specific Case Report Forms (CRFs) will be created in the Online Collaborative Research Environment (OnCore). All electronic data systems and devices should maintain a security system that prevents unauthorized access. All participants must be registered in the OnCore database, allowing the Stanford SRC to judge the aggregate accrual and stopping rules for the study.
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10.7 ethical conduct of the

The study will be conducted in accordance with legal and regulatory requirements, as well as the general principles set forth in the International Ethical Guidelines for Biomedical Research Involving Human Patients (Council for International Organizations of Medical Sciences 2002), Guidelines for Good Clinical Practice (International Conference on Harmonization 1996), and the Declaration of Helsinki (World Medical Association 2008). In addition, the study will be conducted in accordance with the protocol, the International Conference on Harmonization guideline on Good Clinical Practice, and applicable local regulatory requirements and laws.
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11. study discontinuation criteria

Premature termination of this study may occur because of a regulatory authority decision, change in the opinion of the IRB/IEC, drug safety problems, or at the discretion of utomilumab manufacturer Pfizer. In addition, Pfizer retains the right to discontinue development of utomilumab at any time. If a study is prematurely terminated or discontinued, Pfizer will promptly notify the Sponsor-investigator. As directed by Pfizer, all study materials must be collected and all CRFs completed and submitted to the Sponsor-investigator to the greatest extent possible.
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12. publications by investigators

To ensure against inadvertent disclosure of Confidential Information or unprotected Inventions, the Sponsor-investigator will provide Pfizer an opportunity to review any proposed publication or other type of disclosure before it is submitted or otherwise disclosed. The Sponsor-investigator will provide manuscripts, abstracts, or the full text of any other intended disclosure (poster presentation, invited speaker or guest lecturer presentation, etc) to Pfizer at least 30 days before they are submitted for publication or otherwise disclosed. If any patent action is required to protect intellectual property rights, the Sponsor-investigator agrees to delay the disclosure for a period not to exceed an additional 60 days. The Sponsor-investigator will, on request, remove any previously undisclosed Confidential Information (other than the Study results themselves) before disclosure.
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13. data analysis/statistical methods 13.1

All clinical research data generated by this protocol will be captured in electronic case report forms (CRFs) generated using REDCap software. 1. Full Analysis Set The full analysis set includes all enrolled subjects.
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2. safety analysis set

The safety analysis set includes all enrolled subjects who receive at least one dose of study medication.
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3. dlt evaluable set

All enrolled subjects who are eligible, receive study treatment and who either experience DLT during the first 2 cycles, or complete the 2-cycle observation period. Subjects who are lost to follow-up before completion of first 2 cycles due to reasons unrelated to treatment related adverse events are not evaluable for DLT.
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4. response analysis set

All enrolled subjects who are eligible for the study and receive study treatment, have adequate baseline tumor assessments and at least 1 on-study tumor assessment. Subjects who are treated and removed from study prior to on-study tumor assessment because of disease progression will be considered evaluable for efficacy and counted as failures. 5. Pharmacokinetic/Immunogenicity Sets The pharmacokinetic/ADA concentration population is defined as all enrolled subjects who have been treated and have at least one post-dose concentration measurement of either utomilumab or ado-trastuzumab emtansine or trastuzumab. 6. Biomarker Analysis Set Treated subjects who have baseline and at least 1 on-study biomarker assessment.
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13.2 statistical methods and sample

Overall study population is up to 30 subjects, to achieve 25 evaluable subjects. Statistical analyses of this non-randomized, phase 1B study will be primarily descriptive in nature. Formal statistical methods will not be used to determine the number of subjects per cohort in this phase 1B study. Summary statistics for discrete variables will be provided as frequencies and for continuous variables as the mean, standard deviation, median, and ranges. In Cohort 1 Expansion, utomilumab will be given IV at the RP2D (utomilumab 100 mg IV) in combination ado-trastuzumab emtansine up to a total of 17 evaluable subjects who received utomilumab plus ado-trastuzumab emtansine (up to 5 inevaluable subjects may be replaced). Cohort 2 (utomilumab plus trastuzumab) was closed in January 2020 with 5 total subjects enrolled. If 1 or more responses are observed, it will be recommended to conduct a future formal phase 2 trial under a separate protocol.
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13.2.1 accrual considerations

There are approximately 600 new breast cancer patients seen annually at the Stanford Cancer Institute. It is estimated that half of these cases are metastatic and 20% are HER2-positive.
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13.3 efficacy analysis

Tumor response will be presented in the form of subject data listings that include, but are not limited to, tumor type, received (maximum) dose, overall tumor response at each visit, and best overall response. In addition, disease progression date, death date, date of first response, and last tumor assessment date will be listed, together with DR and PFS for the expansion cohort. Kaplan-Meier plot will be created for DR, TTR and PFS in the expansion cohort.
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13.4 analysis of pharmacokinetics and

Ctrough and Cmax for utomilumab and ado-trastuzumab emtansine or trastuzumab will be summarized descriptively (n, mean, SD, CV, median, minimum, maximum, geometric mean, its associated CV, and 95% confidence interval) by dose, cycle, and day. Dose normalized parameters (eg, Cmax, Ctrough) will be reported as appropriate. The trough concentrations for utomilumab and ado-trastuzumab emtansine or trastuzumab will be plotted for each dose using a box whisker plot by cycle and day in order to assess the attainment of steady state.
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13.4.2. analysis of immunogenicity data

ADA/neutralizing antibody (Nab) data will be listed and summarized for each dosing interval for utomilumab, ado-trastuzumab emtansine, or trastuzumab. The percentage of subjects with positive ADA and neutralizing antibodies each will be summarized by dose. For subjects with positive ADA, the magnitude (titer), time of onset, and duration of ADA response may also be described, if data permit. The effect of ADA on utomilumab, ado-trastuzumab emtansine or trastuzumab concentrations will be evaluated if data permit.
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13.4.3. analysis of biomarker endpoints

For CD8 and HER-2 as wells other exploratory biomarkers in tumor biopsy, summary statistics (eg, the mean and standard deviation, median, and minimum/maximum levels of continuous, and frequencies and percentages of categorical biomarker measures) will be determined at baseline and post-treatment as appropriate. For each pair of specimens, the percent change from baseline of these same parameters will also be calculated. Data from biomarker assays may be analyzed using graphical methods and descriptive statistics such as linear regression, t-test, and analysis of variance (ANOVA). The statistical approach will examine correlations of biomarker results with pharmacokinetic parameters and measures of anti-tumor efficacy.
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13.4.4. population pharmacokinetic analysis or

Pharmacokinetic and pharmacodynamic data from this study may be analyzed using modeling approaches and may also be pooled with data from other studies to investigate any association between utomilumab and ado-trastuzumab emtansine/trastuzumab exposure and biomarkers or significant efficacy/safety endpoints. The results of these analyses, if performed, may be reported separately.
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13.5 safety analysis 13.5.1 analysis

DLT is the primary endpoint of the study. Analyses of DLT are based on the DLT-evaluable set. The occurrence of DLTs and Adverse Events constituting DLTs will be summarized and listed per dose for subjects.
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13.5.2 analysis of secondary safety

Adverse Events (AEs) will graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5 and coded using the Medical Dictionary for Regulatory Activities (MedDRA). The focus of AE summaries will be on Treatment Emergent Adverse Events, those with initial onset or increasing in severity after the first dose of study treatment. The number and percentage of subjects who experienced any AE, serious AE (SAE), treatment-related AE, and treatment-related SAE will be summarized according to worst toxicity grades. The summaries will present AEs both on the entire study period and by cycle (Cycle 1 and Cycles beyond 1). The Sponsor-investigator will report all unanticipated problems involving risks to human subjects or others to the IRB of record and to the Stanford SCI Data and Safety Monitoring Committee (DSMC).
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laboratory test abnormalities

The number and percentage of subjects who experienced laboratory test abnormalities will be summarized according to worst toxicity grade observed for each laboratory assay. The analyses will summarize laboratory tests both on the entire study period and by cycle (Cycle 1 and Cycles beyond 1). Shift tables will be provided to examine the distribution of laboratory toxicities. For laboratory tests without CTCAE grade definitions, results will be categorized as normal, abnormal, or not done.
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14. references

1. Barok M, Tanner M, Köninki K, Isola J. Trastuzumab-DM1 causes tumour growth inhibition by mitotic catastrophe in trastuzumab-resistant breast cancer cells in *vivo*. Breast Cancer *Research*. 2011,13(2),R46. doi:10.1186/bcr2868 2. Broll K, Richter G, Pauly S, et al. "CD137 expression in tumor vessel walls. High correlation with malignant tumors. Am J Clin *Pathol*. Apr 2001;115(4):543-549.  
3. Chan FK. Three is better than one: pre-ligand receptor assembly in the regulation of TNF
receptor signaling. Cytokine. 2007 Feb;37(2):101-107.  
4. Croft M. The role of TNF superfamily members in T-cell function and diseases.  
Nat Rev *Immunol*. Apr 2009;9(4):271-285.  
5. English DP, Bellone S, Schwab CL, et al. "T-DM1, a novel antibody-drug conjugate, is highly effective against primary HER2 overexpressing uterine serous carcinoma in *vitro* and in vivo. Cancer *Medicine*. 2014 doi:10.1002/cam4.274.  
6. Fisher TS, Kamperschroer C, Oliphant T, et al. "Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. Cancer Immunol *Immunother*. 2012;61:1721-33.  
7. Furtner M, Straub RH, Krüger S, Schwarz H. Levels of soluble CD137 are enhanced in sera of leukemia and lymphoma patients and are strongly associated with chronic lymphocytic leukemia. *Leukemia*. May 2005;19(5):883-885.  
8. Hentschel N, Krusch M, Kiener PA, et al. "Serum levels of sCD137 (4-1BB) ligand are prognostic factors for progression in acute myeloid leukemia but not in non-Hodgkin's lymphoma. Eur J Haematol. Aug 2006;77(2):91-101.  
9. Houot R, Goldstein MJ, Kohrt HE. Therapeutic effect of CD137 immunomodulation in lymphoma and its enhancement by Treg depletion. *Blood*. 15 Oct 2009;114(16):3431-3438. Epub 29 Jul 2009.  
10. Junttila TT, Li G, Parsons K, et al. "Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Research and *Treatment*. 2011;128(2),347–356. doi:10.1007/s10549-010-1090-x 11. Kohrt HE, Houot R, Weiskopf K, et al. "Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J Clin *Invest*. 2012;122(3),1066–1075. doi:10.1172/JCI61226 61226.  
12. Kohrt HE, Houot R, Goldstein MJ.CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies. *Blood*. 24 Feb 2011;117(8):2423-2432. Epub 30 Dec 2010.  
13. Kohrt HE, Colevas AD, Houot R, et al. "Targeting CD137 enhances the efficacy of cetuximab. J Clin *Invest*. 2014 doi:10.1172/JCI73014 14. Olofsson PS, Söderström LA, Wågsäter D, et al. "CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice. *Circulation*. 11 Mar 2008;117(10):1292-1301.  
15. Park S, Jiang Z, Mortenson ED, et al. "The Therapeutic Effect of Anti-HER2/neu Antibody Depends on Both Innate and Adaptive Immunity. Cancer *Cell*. 2010;18(2),160–170. doi:10.1016/j.ccr.2010.06.014 16. Sabbagh L, Pulle G, Liu Y, et al. "ERK-dependent Bim modulation downstream of the 4-1BB-TRAF1 signaling axis is a critical mediator of CD8 T-cell survival in *vivo*. J *Immunol*. 15 Jun 2008;180(12):8093-8101.  
17. Seaman S, Stevens J, Yang MY, et al. "Genes that distinguish physiological and pathological angiogenesis. Cancer *Cell*. Jun 2007;11(6):539-554.  
18. Segal, N, Gopal, A, Bhatia, S, et al. "A phase 1 study of PF-05082566 (anti-4-1BB) in patients with advanced cancer." Journal of Clinical *Oncology*. 2014;32(15suppl):3007 19. Vinay DS, Cha K, Kwon BS. Dual immunoregulatory pathways of 4-1BB signaling.  
J Mol Med. Sep 2006;84(9):726-736.  
20. Wang C, Lin GH, McPherson AJ, et al. "Immune regulation by 4-1BB and 4-1BBL:
complexities and challenges. Immunol Rev. May 2009;229(1):192-215.  
21. Zhang X, Voskens CJ, Sallin M, et al. "CD137 promotes proliferation and survival of human B-cells." J *Immunol*. 15 Jan 2010;184(2):787-795. Epub 11 Dec 2009 .
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appendix 1. determination of efficacy

Lesions that can be accurately measured in at least one dimension.  
Lesions with longest diameter twice the slice thickness and at least 10 mm or greater when assessed by CT or MRI (slice thickness 5 to 8 mm).  
Lesions with longest diameter at least 20 mm when assessed by chest X-ray.  
Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.  
Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
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note the shortest axis is

Non-measurable disease includes lesions too small to be considered measurable (including nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured with calipers, abdominal masses identified by physical exam that are not measurable by reproducible imaging techniques.  
Bone disease: Bone disease is non-measurable with the exception of soft tissue components that can be evaluated by CT or MRI and meet the definition of measurability at baseline.  
Previous local treatment: A previously irradiated lesion (or lesion subjected to other local treatment) is non-measurable unless it has progressed since completion of treatment.
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normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should not be recorded either as target or non-target disease. Cystic lesions thought to represent cystic metastases can be measurable lesions, if they meet the specific definition above. If non-cystic lesions are also present, these are preferred as target lesions.  
Normal nodes: Nodes with short axis < 10 mm are considered normal and should not be recorded or followed either as measurable or non-measurable disease.
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recording tumor assessments

All sites of disease must be assessed at baseline. Baseline assessments should be done as close as possible prior to study start. For an adequate baseline assessment, all required scans must be done within 28 days prior to treatment and all disease must be documented appropriately. If baseline assessment is inadequate, subsequent statuses generally should be indeterminate.
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target lesions

All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, representative of all involved organs, should be identified as target lesions at baseline. Target lesions should be selected on the basis of size (longest lesions) and suitability for accurate repeated measurements. Record the longest diameter for each lesion, except in the case of pathological lymph nodes for which the short axis should be recorded. The sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions at baseline will be the basis for comparison to assessments performed on study.  
If two target lesions coalesce the measurement of the coalesced mass is used. If a large target lesion splits, the sum of the parts is used.  
Measurements for target lesions that become small should continue to be recorded. If a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is considered to have disappeared;; otherwise a default value of 5 mm should be recorded.
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note when nodal lesions decrease

All non-measurable disease is non-target. All measurable lesions not identified as target lesions are also included as non-target disease. Measurements are not required but rather assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT INCREASED, INCREASED. Multiple non-target lesions in one organ may be recorded as a single item on the case report form (eg, 'multiple enlarged pelvic lymph nodes' or 'multiple liver metastases').
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objective response status at each

Disease sites must be assessed using the same technique as baseline, including consistent administration of contrast and timing of scanning. If a change needs to be made the case must be discussed with the radiologist to determine if substitution is possible. If not, subsequent objective statuses are indeterminate.
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target disease

Complete Response (CR): Complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis < 10 mm). All target lesions must be assessed.  
Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter is used in the sum for target nodes, while the longest diameter is used in the sum for all other target lesions. All target lesions must be assessed.  
Stable: Does not qualify for CR, PR or Progression. All target lesions must be assessed.  
Stable can follow PR only in the rare case that the sum increases by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer holds.  
Objective Progression (PD): 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.  
Indeterminate. Progression has not been documented; and o One or more target measurable lesions have not been assessed; or o Assessment methods used were inconsistent with those used at baseline; or
o One or more target lesions cannot be measured accurately (eg, poorly visible unless due to being too small to measure); or o One or more target lesions were excised or irradiated and have not reappeared or increased.
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non-target disease

CR: Disappearance of all non-target lesions and normalization of tumor marker levels.  
All lymph nodes must be 'normal' in size (< 10 mm short axis).  
Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above the normal limits.  
PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor burden must increase sufficiently to merit discontinuation of therapy. In the presence of SD or PR in target disease, progression due to unequivocal increase in non-target disease should be rare.  
Indeterminate: Progression has not been determined and one or more non-target sites were not assessed or assessment methods were inconsistent with those used at baseline.
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new lesions

The appearance of any new unequivocal malignant lesion indicates PD. If a new lesion is equivocal, for example due to its small size, continued assessment will clarify the etiology. If repeat assessments confirm the lesion, then progression should be recorded on the date of the initial assessment. A lesion identified in an area not previously scanned will be considered a new lesion.
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supplemental investigations

If CR determination depends on a residual lesion that decreased in size but did not disappear completely, it is recommended the residual lesion be investigated with biopsy or fine needle aspirate. If no disease is identified, objective status is CR. If progression determination depends on a lesion with an increase possibly due to necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify status.
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subjective progression

Subjects requiring discontinuation of treatment without objective evidence of disease progression should not be reported as PD on tumor assessment CRFs. This should be indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health Status. Every effort should be made to document objective progression even after discontinuation of treatment.  
| Objective Response Status at each Evaluation                                                           |                                          |             |                  |
|--------------------------------------------------------------------------------------------------------|------------------------------------------|-------------|------------------|
| Target Lesions                                                                                         | Non-target Lesions                       | New Lesions | Objective status |
| CR                                                                                                     | CR                                       | No          | CR               |
| CR                                                                                                     | Non-CR/Non-PD                            | No          | PR               |
| CR                                                                                                     | No                                       |             |                  |
| Indeterminate or Missing                                                                               | PR                                       |             |                  |
| PR                                                                                                     | Non-CR/Non-PD, Indeterminate, or Missing | No          | PR               |
| SD                                                                                                     | Non-CR/Non-PD, Indeterminate, or Missing | No          | Stable           |
| Indeterminate or                                                                                       | Non-PD                                   | No          | Indeterminate    |
| Missing PD                                                                                             | Any                                      | Yes or No   | PD               |
| Any                                                                                                    | PD                                       | Yes or No   | PD               |
| Any                                                                                                    | Any                                      | Yes         | PD               |
| Adapted from: Eisenhauer EA, Therasse P, Bogaerts J, et al. "New response evaluation criteria in solid |                                          |             |                  |  
Adapted from: Eisenhauer EA, Therasse P, Bogaerts J, et al. "New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)." Eur J *Cancer*. Jan 2009;45(2):228-247.
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appendix 2 ecog performance status

0 Fully active, able to carry on all pre-disease activities without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, eg, light house work or office work 2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours 3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 5 Dead From: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin *Oncol*. 1982;5:649–655. 090177e1869e9927\  
| Appendix 3: Schedule of Activities  Screening                                                         | On Treatment (1 Cycle = 21 days)   | Post-Treatment             |                                                                                              |                             |                              |                              |                                                  |     |     |
|-------------------------------------------------------------------------------------------------------|------------------------------------|----------------------------|----------------------------------------------------------------------------------------------|-----------------------------|------------------------------|------------------------------|--------------------------------------------------|-----|-----|
| Protocol Activity                                                                                     |                                    |                            |                                                                                              |                             |                              |                              |                                                  |     |     |
| (Cycle Day relative to utomilumab dosing)                                                             | Cycle 1                            | Cycle 2                    | Cycles ≥ 3 End of Treatment /  withdrawal  (within 28 days  from final dose) 28 Follow-Up 30 |                             |                              |                              |                                                  |     |     |
| (Within  28 days of  Cycle 1,  Day 0)                                                                 | Day 1 (± 2  business  days)        |                            |                                                                                              |                             |                              |                              |                                                  |     |     |
| Baseline documentation Informed Consent 1                                                             | X                                  |                            |                                                                                              |                             |                              |                              |                                                  |     |     |
| Medical/Tumor History 2                                                                               | X                                  |                            |                                                                                              |                             |                              |                              |                                                  |     |     |
| Physical Examination (within 24 hours prior  to start of each cycle) 3                                | X                                  | X                          | X                                                                                            | X                           | X                            | (X)                          |                                                  |     |     |
| ECOG Performance Status (± 3 days) 4                                                                  | X                                  | X                          | X                                                                                            | X                           | X                            | (X)                          |                                                  |     |     |
| Safety Labs/ Measurements Vital signs (BP and pulse, within 24 hours  prior to start of each cycle) 5 | X                                  | X                          | X                                                                                            | X                           | X                            | X                            | X                                                | X   | (X) |
| 12 lead ECG (± 3 days) 6                                                                              | X                                  | X                          | X                                                                                            | X                           | (X)                          |                              |                                                  |     |     |
| Hematology (CBC, differential, platelets) 7                                                           | X                                  | X                          | X                                                                                            | X                           | X                            | X                            | X                                                | (X) |     |
| Coagulation (PT/INR and PTT) 8                                                                        | X                                  | X                          | X                                                                                            | X                           | X                            | (X)                          |                                                  |     |     |
| Blood Chemistry 9                                                                                     | X                                  | X                          | X                                                                                            | X                           | X                            | X                            | X                                                | (X) |     |
| Urinalysis 10                                                                                         | X                                  | X                          | (X)                                                                                          |                             |                              |                              |                                                  |     |     |
| Hepatitis B and C testing 11                                                                          | X                                  |                            |                                                                                              |                             |                              |                              |                                                  |     |     |
| Pregnancy test 12                                                                                     | X                                  | X                          | X                                                                                            | X                           | X                            | (X)                          |                                                  |     |     |
| Endocrine function 13                                                                                 | X                                  | Day 0 (± 2 business  days) | Day 1 (± 2 business  days)                                                                   | Day 8  (± 2 business  days) | Day 15  (± 2 business  days) | Day 1  (± 2  business  days) | Cycle 5 Day 1, then every  4 th cycle (± 7 days) |     |     |
| LVEF assessment 14                                                                                    | X                                  | X                          |                                                                                              |                             |                              |                              |                                                  |     |     |
| ≤ 7 days                                                                                              |                                    |                            |                                                                                              |                             |                              |                              |                                                  |     |     |
| Registration 1                                                                                        | before                             |                            |                                                                                              |                             |                              |                              |                                                  |     |     |
| Cycle 1, Day 0                                                                                        |                                    |                            |                                                                                              |                             |                              |                              |                                                  |     |     |
| Treatment Administration of utomilumab 15                                                             | X                                  | X                          | X                                                                                            |                             |                              |                              |                                                  |     |     |
| Administration of  ado-trastuzumab emtansine or trastuzumab 16                                        | X                                  | X                          | X                                                                                            |                             |                              |                              |                                                  |     |     |  
| Screening                                                                                                                                                      | On Treatment (1 Cycle = 21 days)   | Post-Treatment                          |                                                                                              |                              |                              |                                                                      |    |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------|-----------------------------------------|----------------------------------------------------------------------------------------------|------------------------------|------------------------------|----------------------------------------------------------------------|----|
| Protocol Activity                                                                                                                                              |                                    |                                         |                                                                                              |                              |                              |                                                                      |    |
| (Cycle Day relative to utomilumab dosing)                                                                                                                      | Cycle 1                            | Cycle 2                                 | Cycles ≥ 3 End of Treatment /  withdrawal  (within 28 days  from final dose) 28 Follow-Up 30 |                              |                              |                                                                      |    |
| (Within  28 days of  Cycle 1,  Day 0)                                                                                                                          | Day 1 (± 2  business  days)        |                                         |                                                                                              |                              |                              |                                                                      |    |
| Tumor Assessment                                                                                                                                               | Day 0 (± 2 business  days)         | Day 1 (± 2 business  days)              | Day 8  (± 2 business  days)                                                                  | Day 15  (± 2 business  days) | Day 1  (± 2  business  days) | Cycle 4 Day 1, then every  3 rd cycle (± 7 days) while  on treatment |    |
| CT scan with contrast (chest, abdomen, +  pelvis) plus radionucleide bone scan or CT/PET with contrast. CNS imaging by CT  or MRI if CNS metastasis present 17 | X                                  | X                                       |                                                                                              |                              |                              |                                                                      |    |
| Pharmacokinetic, Pharmacodynamic Assessments Blood for utomilumab PK 6, 18                                                                                     | X                                  | X                                       | X                                                                                            | X                            |                              |                                                                      |    |
| Blood for ado-trastuzumab emtansine / trastuzumab PK 6, 19                                                                                                     | X                                  | X                                       | X                                                                                            | X                            |                              |                                                                      |    |
| Blood for biomarkers linked with  immunomodulation / cytokine release 20                                                                                       | X                                  | X                                       | X                                                                                            | X                            | X                            | X                                                                    | X  |
| Pharmacodynamic assessment of lymphocyte  subpopulation 21                                                                                                     | X                                  | X                                       | X                                                                                            |                              |                              |                                                                      |    |
| T cell receptor assessment 22                                                                                                                                  | X                                  | X                                       | X                                                                                            |                              |                              |                                                                      |    |
| Blood for utomilumab immunogenicity  (ADA) testing 23                                                                                                          | X                                  | X                                       | X                                                                                            | X                            | X                            |                                                                      |    |
| Blood for ado-trastuzumab emtansine / trastuzumab immunogenicity                                                                                               | X                                  | X                                       | X                                                                                            | X                            | X                            |                                                                      |    |
| (ADA) testing 24 Blood for exploratory biomarkers 25                                                                                                           | X                                  | X                                       | X                                                                                            |                              |                              |                                                                      |    |
| Optional tumor biopsy for biomarker  assessment 26                                                                                                             | X                                  | X (Cycle 4)                             |                                                                                              |                              |                              |                                                                      |    |
| Other Clinical Assessment Adverse event 27                                                                                                                     | X                                  | Monitor and record at every study visit | X                                                                                            | X                            |                              |                                                                      |    |
| Concomitant medication 28                                                                                                                                      | X                                  | Monitor and record at every study visit | X                                                                                            |                              |                              |                                                                      |    |
| Note: 1 cycle = 21 days ± 2 business days                                                                                                                      |                                    |                                         |                                                                                              |                              |                              |                                                                      |    |  
1. Informed Consent: Must be obtained prior to undergoing any study specific procedure and may occur prior to the 28-day screening period. Registration will considered to be signed informed consent with triple-signed eligibility checklist, with the final signature being the Stanford Principal Investigator or his designee. 2. Medical History/Tumor History: To be collected within 28 days prior to registration (registration is defined as signed informed consent plus PI-signed confirmation of all eligibility criteria). Includes history of other diseases (active or resolved) and concomitant illnesses. Include oncology history; information on prior regimens (including dosing and duration of administration, description of best response observed, recurrence date), surgery and radiation therapy. 3. Physical Examination: Includes an examination of major body systems. Weight for the purposes of dose calculation will be recorded at screening and within 7 days pre-dose Day 1 of each cycle. Weight may not be collected at End of Treatment. Height will be measured at baseline. 4. ECOG PS: ECOG performance scale is available as Appendix 6 in the full protocol. 5. Blood pressure (BP) and pulse rate to be recorded in supine or sitting position. 6. 12-lead ECG **and pharmacokinetics:** At each time point, a 12-lead ECG will be performed to determine QTc. ECGs and blood sample draws for PK and other research assessments should be done at 2 separate time points prior and post-infusion when applicable, with no preference to the order of performance. ECGs will be performed at screening, on Day 1 of Cycles 1 and 2 before and at the end of utomilumab infusion. If the QTc interval is prolonged (> 500 msec), then the ECGs should be reevaluated by a qualified person at the center for confirmation. Additional ECGs may be performed as clinically indicated. 7. Hematology: No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date. On treatment, to be performed prior to dosing with study medications unless otherwise indicated. If during the first cycle of treatment a Grade 4 hematologic event is evident, the hematology assessment should be repeated at least on or after 7 days later to assess for events qualifying as DLT. 8. Coagulation: No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date. On treatment, to be performed prior to dosing with study medications unless otherwise indicated. 9. Blood Chemistry: Blood chemistry collection as shown for first cycle; thereafter, blood chemistry collection required only within 72 hours prior to beginning of each cycle. 10. Urinalysis: Conducted for all subjects at screening. During the treatment period to be performed only when clinically indicated. If protein ≥ 2+ by semiquantitative method (eg, urine dipstick), protein will be quantified by 24-hour urine collection. Urine reflex microscopy is recommended whenever urine multitest dipstick is positive for blood or protein. 11. Hepatitis B and C Testing: Conduct tests for hepatitis B surface antigen, core antibody, and anti-hepatitis C. Other standard tests may be conducted to confirm an active hepatitis infection. 12. Pregnancy Test: For female subjects of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, and assayed in a certified laboratory, will be performed on 2 separate occasions prior to starting study treatment: once at the start of screening and once at the baseline visit (except if screening and baseline are within 2 **days of each other**). Negative results for the baseline pregnancy must be obtained and documented before ado-trastuzumab emtansine administration. Following a negative pregnancy result at screening, appropriate contraception must be commenced. Pregnancy tests to be routinely repeated at every cycle (eg, on Day 1) during the active treatment period. Additional pregnancy test to be repeated whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected. 13. Endocrine Function: Assessed by medical history, physical examination, and routine laboratory parameters (eg, blood chemistries) for endocrine function (including but not limited to TSH, ACTH, and cortisol levels), and as medically appropriate may include assessment for hypopituitarism and hypoadrenalism. Conducted for all subjects at screening/baseline, and when clinically indicated during the treatment period. 14. **LVEF Assessment:** Performed at screening; at Cycle 5 Day 1 (± 7 days); every 4 cycles (± 7 days) thereafter; and at end of treatment. 15. Utomilumab **Administration:** Treatment will be administered in a 3-week cycle (ie, 21-day cycle). Utomilumab will be administered as a 1-hour intravenous infusion (± 15 minutes) on Day 1 of each cycle. When both utomilumab and ado-trastuzumab emtansine/trastuzumab are administered, ado-trastuzumab emtansine/trastuzumab will be administered first, followed within 30 minutes (± 15 min) by utomilumab infusion. 16. Ado-trastuzumab emtansine or trastuzumab Administration: Treatment will be administered in a 3-week cycle (ie, 21-day cycle), by intravenous infusion. The first infusion of ado-trastuzumab emtansine or trastuzumab on-study will be over 90 minutes (± 30 minutes) on Cycle 1 Day 0. Subsequent infusions will be administered over 30 ± 15 minutes as tolerated. 17. Tumor assessment: Assessment of response will be made using RECIST v1.1. Antitumor activity will be assessed through radiological tumor assessments conducted a baseline, on treatment every 9 weeks and whenever disease progression is suspected (eg, symptomatic deterioration). To be repeated at End of Treatment/Withdrawal only if not done in the previous 9 weeks. Confirmation of response (CR/PR) should be done at least 4 weeks after the initial response. The allowable time window for disease assessments is ± 7 business days, on treatment, starting from C1D1. Timing should follow calendar days and should not be adjusted for delays in cycle starts. Tumor assessments performed after the screening period should consist of 1) CT and/or MRI of the chest/abdomen/pelvis; 2) bone scan or PET scan if bone metastases identified during the screening period are clinically indicated by the treating physician; and 3) CNS imaging clinically indicated by the treating physician. 18. Blood for utomilumab **pharmacokinetics:** Blood samples (tube type and quantity per lab manual) will be collected as follow: Cycles 1 to 3 on Day 1 at pre-dose and at the end of utomilumab infusion; From Cycle 4 onwards, it will be collected on Day 1 at pre-dose of every 3 cycles (eg, Cycle 4; Cycle 7; Cycle 10; etc). For subjects discontinuing from the study, a PK sample should be collected at the End of Treatment assessment. 19. Blood for ado-trastuzumab emtansine or trastuzumab pharmacokinetics: Blood samples (tube type and quantity per lab manual) will be collected as follows: Cycle 1 on Day 0 at pre-dose and a the end of ado-trastuzumab emtansine or trastuzumab infusion; Cycle 2 to 3 on Day 1 at pre-dose and at the end of ado-trastuzumab emtansine or trastuzumab infusion. From Cycle 4 onwards, it will be collected on Day 1 at pre-dose of every 3 cycles (eg, Cycle 4; Cycle 7; Cycle 10; etc). For subjects discontinuing from the study, a PK sample should be collected at the End of Treatment assessment. 20. Blood for Immunomodulation/Cytokine Release Biomarkers: Blood samples (tube type and quantity per lab manual) will be collected as follows: at Screening, Cycles 1 on Day 0 at pre-dose and at the end of infusion of ado-trastuzumab emtansine or trastuzumab; Cycles 1 on Day 1 at pre-dose and at the end of infusion of utomilumab; on Day 8 and Day 15 of Cycle 1; on Day 1 of Cycle 2 at pre-dose; at end of treatment. 21. Blood for Pharmacodynamic Assessment of Lymphocyte Subpopulation: Blood samples (tube type and quantity per lab manual) for the isolation and analysis of lymphocytes subpopulation will be collected at screening, on Cycle 2 Day 1 at pre-dose, and at end of treatment.  
22. **Blood for T cell Receptor Assessment**: Blood samples (tube type and quantity per lab manual) for the isolation and analysis of T-cell receptors will be collected at screening, on Cycle 2 Day 1 at pre-dose, and at end of treatment. 23. Blood for utomilumab **Immunogenicity Testing:** Blood samples (tube type and quantity per lab manual) for utomilumab immunogenicity testing will be collected on Cycles 1 to 3 on Day 1 at pre-dose. From Cycle 4 onwards, blood samples will be collected on Day 1 at pre-dose every 4 cycles (eg, Cycle 8; Cycle 12; Cycle 16; etc). For subjects discontinuing study drug treatment, immunogenicity samples should be collected at the End of Treatment and at Follow-Up. If ADAs are detected, additional samples may be collected approximately every 9 weeks (coinciding with disease assessment visit) until ADA levels return to baseline. 24. Blood for ado-trastuzumab emtansine/trastuzumab Immunogenicity Testing: Blood samples (tube type and quantity per lab manual) for ado-trastuzumab emtansine or trastuzumab immunogenicity testing will be collected on Cycles 1 on Day 0 at pre-dose and on Cycle 2 and 3 on Day 1 at pre-dose. From Cycle 4 onwards, blood samples will be collected on Day 1 at pre-dose every 4 cycles (eg, Cycle 8; Cycle 12; Cycle 16; etc). For subjects discontinuing study drug treatment, immunogenicity samples should be collected at the End of Treatment and at Follow Up. If ADAs are detected, additional samples may be collected approximately every 9 weeks (coinciding with disease assessment visit) until ADA levels return to baseline. 25. Blood for Exploratory Biomarkers: Blood samples (tube type and quantity per lab manual) will be collected at Screening, on Cycle 2 Day 1 at pre-dose, and at end of treatment. 26. Tumor Biopsy for Biomarker Assessment: See Appendix 4. A recent tumor biopsy is requested be provided at enrollment. An archival biopsy may be acceptable per eligibility criteria (see inclusion criteria). Tissue blocks are preferred, but if not available at least 20 unstained slides are suggested. For eligibility, if no unstained slides remain, stained pathology slides should be reviewed at the treating institution. A tumor biopsy at Day 1, Cycle 4 (± 14 days) is requested unless clinically not feasible. 27. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each scheduled or unscheduled visit, including at end-of-treatment and during follow-up, using NCI CTCAE v5. Subjects must be followed for AEs for 28 days after the last treatment administration or until all drug-related toxicities have resolved, whichever is later; or earlier than 28 days should the subject commence another anticancer therapy in the meantime. For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that the subject provides informed consent, which is obtained prior to the subject's participation in the study, ie, prior to undergoing any study-related procedure and/or receiving investigational product, through and including 60 calendar days after the last administration of the investigational products and before initiation of a new anti-cancer treatment. The prolonged follow up is due to the pharmacokinetic properties of the investigational product utomilumab. SAEs experienced by a subject after the active reporting period has ended should be reported to the Sponsor if the Investigator becomes aware of them; at a minimum, all SAEs that the Investigator believes have at least a reasonable possibility of being related to study drug are to be reported to the Sponsor. AEs (serious and non-serious) should be recorded on the Case Report Form (CRF) from the time the subject has taken at least one dose of study treatment through last subject visit (Day 28 after last dose). If a subject begins a new anticancer therapy, the AE reporting period for non-serious AEs ends at the time the new treatment is started. Pregnancy or breast feeding that occur during the trial, within 28 days after the cessation of utomilumab if the subject begins a new anticancer therapy, whichever is earlier, should be reported as SAE. 28. Concomitant Medications: Concomitant medications will be recorded from 28 days prior to the start of study treatment and up to 28 days after the last dose of study treatment. Concomitant medications will be collected at each scheduled or unscheduled visit, including at end-of-treatment. All concomitant medications should be recorded in the CRF including supportive care drugs (eg, anti-emetic treatment and prophylaxis), and the drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions). 29. End of Treatment: To be performed 28 days (± 7 days) after the last dose of study drug. Obtain these assessments if not completed during the previous week on study, (during the previous 9 weeks on study, for tumor assessments).  
30. Follow-Up: Subjects should be evaluated, including for adverse events, up to 60 days after last dose of study treatment. Subjects continuing to experience toxicity following discontinuation of study treatment will continue to be followed including for adverse events, at least every 3 weeks until resolution or determination, in the clinical judgment of the Investigator, that no further improvement is expected. Adverse events will not be collected after resolution of treatment-related toxicities or 60 days after last dose of study treatment, whichever is later. Subjects whose disease has not progressed at the end of treatment will enter into disease follow-up. During this follow up period, subjects will have disease assessments performed every 9 weeks (± 7 days). Once subjects have exhibited disease progression or began a new anticancer therapy, or 6-month follow-up from the date of the last dose of the study drug, whichever occurs first, they will be withdrawn from the study.
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appendix 4 tumor biopsy recommendations

Optional tumor biopsies for subjects with accessible tumors are strongly encouraged. Suggested time points are as follows: Baseline pre-treatment, and on Cycle 4 Day 1 ± 14 days. These are suggested time points; but tissue sample collection may be obtained at any time point as feasible (eg, during drainage of pleural fluid for symptom relief, etc). Tissue collection kits will be provided: 1. Tumor specimens will be obtained from accessible tumor sites as follows:  
a. Fine Needle Aspiration (FNA) -- to be used only if core biopsy is not allowed or if not feasible. The needle aspirate biopsies will be apportioned by pathology into multiple types of media for assessment. Portions of specimen must be prioritized in the following order at the discretion of the pathologist involved in the case/responsible for the trial: i. Smears for histology and diagnosis ii. Tissue frozen at -80ºC for RNA/DNA isolation/analysis iii. Fresh frozen tissue for optimum cutting temperature (OCT) compound.  
b. Core biopsy: 2 to 3 large bore (3 mm) needle biopsies of accessible, involved sites will be made at the time points suggested above. The needle aspirate biopsies will be apportioned by pathology into multiple types of media for assessment. Portions of specimen must be prioritized in the following order at the discretion of the pathologist reviewing the case /responsible for the trial:
i. Portion of core submitted for formalin-fixed, paraffin-embedded (FFPE) processing to be used for histology and diagnosis, for FFPE compatible immunohistochemistry and in situ hybridization ii. Tissue frozen at -80ºC for RNA/DNA isolation/analysis iii. Fresh frozen tissue embedded in optimum cutting temperature (OCT) compound for immunohistochemistry and in situ hybridization that requires fresh frozen tissue, and for Western blot analysis.  
iv. Viably frozen tumor cells, dissociated for other cellular experimentation and for flow analysis to determine percentage of tumor cells vs infiltrating lymphocytes, etc.  
c. Excisional biopsy: Tissue will be taken and apportioned by pathology into multiple types of media for assessment. Portions of specimen must be prioritized in the following order and will be at the discretion of the pathologist reviewing the case/responsible for the trial: i. Portion of the specimen will be submitted for FFPE processing to be used for histology and diagnosis, determination of treatment effect (degree of necrosis compared to original diagnostic material), determination of local variations (periphery of tumor vs center) for FFPE compatible immunohistochemistry and in situ hybridization.  
ii Tissue frozen at -80ºC for RNA/DNA isolation/analysis iii. Fresh frozen tissue embedded in optimum cutting temperature (OCT) compound for immunohistochemistry and in situ hybridization that requires fresh frozen tissue, and for Western blot analysis.  
iv. Viably frozen tumor cells, dissociated for other cellular experimentation and for flow analysis to determine percentage of tumor cells vs infiltrating lymphocytes, etc.  
v. Fresh viable (non-frozen) tissue for consideration for implantation into mice to develop xenograft models and extend tumors for further experimentation.  
d. Paracentesis/thoracocentesis/lumbar puncture: Cells in the fluid obtained from paracentesis/thoracentesis/lumbar puncture will be spun down and cell count taken. Tissue will be taken and apportioned by pathology into multiple types of media for assessment. Portions of specimen must be prioritized in the following order and will be at the discretion of the pathologist reviewing the case/responsible for the trial: i. Smear for histology and diagnosis, eg, determination of percentage of tumor cells vs inflammatory cells.  
ii. Fresh cells for flow analysis to determine percentage of tumor cells vs infiltrating lymphocytes, vs mesothelial cells, etc.
iii. Tissue for RNA/DNA analysis iv. Fresh frozen tissue embedded in optimum cutting temperature (OCT) compound for immunohistochemistry and in situ hybridization that requires fresh frozen tissue, and for Western blot analysis.  
v. Viably frozen tissue for other cellular experimentation  
vi. Remainder of the cell pellet will be submitted for FFPE for FFPE compatible immunohistochemistry and in situ hybridization.
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appendix 5 correlative / special

- Serum and intratumoral biomarkers linked to immunomodulation and cytokine release such as: TNFα; IL-6; IFNγ; CXCL9; CXCL10; IL10; IL-8; IL-4; IL-2; IL-1b; IL-12p70
- Exploratory PD biomarkers expressed by PBMC and intratumoral lymphocytes, such as Ki67, soluble CD137, and markers of T and NK cell phenotype (such as CD3; CD4; CD8; CD25; HLA-DR; CCR7; ICOS; Eomesodermin; CD45RA; CD45RO; CD16; CD56; CD25; CXCR6; TNFSF4; TNFSF7; ITGA2; ITGB7; VCAM1) and quantitation of T-cell receptor sequences;
- Tumor biopsy for analysis of exploratory mechanistic biomarkers such as IHC assessment of tumor-infiltrating lymphocytes and quantitation of T-cell receptor sequences;
- (Optional blood and intratumoral sample) Pharmacogenomic (RNA) analysis of subject PBMC to explore expression of genes that would influence subject response to utomilumab and TDM-1 or trastuzumab, such as EOMES; CDKN2D; TIMP1; FCGR2B; IL1RN; SOCS3; CXCL9; CXCL10; IL1B; IFI16; CCR5; FASLG; CXCR3; IFNG; ICOS; CD40LG; IL2RA; CD80; CCL5; FOXP3; CDC25A,GZMA; IL23A; SOCS1; IL10;
- (Optional blood and intratumoral sample) Pharmacogenetic (DNA) analysis of subject PBMC to explore polymorphisms in genes such as FCGR2A and FCGR3A that could affect response to utomilumab and TDM-1 or trastuzumab  
| Appendix 6. List of Abbreviations: 4-1BB CD137, a member of the tumor necrosis factor (TNF) receptor family.  Alternative names are tumor necrosis factor receptor superfamily member 9  (TNFRSF9) and induced by lymphocyte activation (ILA). AC Adriamycin plus cyclophosphamide chemotherapy ADA Anti-drug antibody ADCC Antibody dependent cellular cytotoxicity AE Adverse event ALT Alanine aminotransferase ANOVA Analysis of variance APC Antigen-presenting cell ASCO American Society of Clinical Oncology AST Aspartate aminotransferase ANC Absolute neutrophil count CFR Code of Federal Regulations CL Clearance CNS Central nervous system CRF Case report form CT Computed tomography CTCAE Common terminology criteria for adverse events DC Dendritic cell DLT Dose-limiting toxicity DR Duration of response DSMC Data safety and monitoring committee ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group FDA Food and Drug Administration FFPE Formalin-fixed paraffin embedded FIH First-in-human FISH Fluorescence in situ hybridization FL Follicular lymphoma FNA Fine needle aspirate GCP Good clinical practice HER2 Human epidermal growth factor receptor 2 IHC Immunohistochemistry ILD Interstitial lung disease IRB Institutional review board IRR Infusion related reaction IV Intravenous LNG-IUS Levonorgestrel-releasing intrauterine system LVEF Left ventricular ejection fraction mAb Monoclonal antibody MAP Mitogen activated protein MCC Merkel Cell CarcinomaIRB-37299 Page 86 of 87 21 September 2020   |
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| MCL         | Mantle cell lymphoma                                                                   |
|-------------|----------------------------------------------------------------------------------------|
| MRI         | Magnetic resonance imaging                                                             |
| MTD         | Maximum tolerated dose                                                                 |
| MUGA        | Multi-gated acquisition                                                                |
| NCI         | National cancer institute                                                              |
| NHL         | Non-Hodgkin's lymphoma                                                                 |
| OCT         | Optimum cutting temperature                                                            |
| PBMC        | Peripheral blood mononuclear cells                                                     |
| PD          | Progressive disease                                                                    |
| PET         | Positron emission tomography                                                           |
| PF-05082566 | Utomilumab, a humanized anti-CD137 monoclonal antibody                                 |
| PFS         | Progression-free survival                                                              |
| PK          | Pharmacokinetics                                                                       |
| PR          | Partial response                                                                       |
| RECIST      | Response evaluation criteria in solid tumors                                           |
| RP2D        | Recommended phase 2 dose                                                               |
| SAE         | Serious adverse event                                                                  |
| SRC         | Scientific review committee                                                            |
| TBI         | Total body irradiation                                                                 |
| T-DM1       | Ado-trastuzumab emtansine, a antibody-drug conjugate of trastuzumab   and maytansine 1 |
| TNF         | Tumor necrosis factor                                                                  |
| TRAF        | Tumor necrosis factor receptor-associated factor                                       |
| TTR         | Time-to-treatment response                                                             |
| Vc          | Volume of distribution                                                                 |