Testing the Safety and Tolerability of the Anti-cancer Drugs Trastuzumab Deruxtecan and Neratinib for Cancers With Changes in the HER2 Gene

Inclusion Criteria:

• Patients must have histologically confirmed malignancy that is metastatic orunresectable with participation in this clinical trial determined to be the bestoption for next treatment in the opinion of the investigator

• Patients must have a solid tumor with HER2-positivity as determined by any one ormore of the following:

• HER2 overexpression defined by IHC 3+

• ERBB2 amplification by ISH or next-generation sequencing as determined by anyCLIA certified lab

• A known HER2 activating mutation

• HER2 overexpression by IHC/ISH will follow histology specific ASCO-CAPguidelines for breast and gastric cancers. For tumor histologies withoutspecific guidelines the following criteria will apply:

• HER2 IHC should be performed first, followed by ISH methods in casesshowing 2+ (equivocal) expression by IHC. Positive (IHC 3+) or negative (IHC 0 or 1+) do not require further ISH testing. Cases with HER2:CEP17ratio ≥ 2 or an average HER2 copy number ≥ 6.0 signals per cell areconsidered positive by ISH

• Known HER2 activating mutations:

• G309A/E

• S310F/Y

• S653C

• V659E

• G660D

• R678Q

• E693K

• Q709L

• L755S/P

• Del. 755-759

• D769Y/H

• G776V/C

• V777L

• V842I

• T862A

• L869R

• H878Y

• All exon 20 insertions, including:

• A771_Y772insYVMA

• A775_G776insYVMA

• Y772_A775dup

• P780_Y781insGSP

• G778_P780dup

• V697L

• T733I

• D769N

• L841V

• L866M

• R896C

• If a different mutation is identified, contact the study chair for conferral.Synonymous mutations are not eligible

• Patients must have received at least 1 prior line of therapy in theadvanced/metastatic setting. No limitation on number of prior therapies; however,patients may not have received neratinib or DS-8201a previously. Prior HER2-targetedtherapy other than neratinib or DS-8201a is allowed (e.g., trastuzumab, pertuzumab,TDM-1, lapatinib, etc.)

• Age >= 18 years. Because no dosing or adverse event data are currently available onthe use of neratinib in combination with DS-8201a in patients < 18 years of age,children are excluded from this study

• Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

• Hemoglobin >= 9.0 g/dL (>= 8.0 g/dL for gastric cancer [GC] only) (within 14 days ofenrollment)

• No transfusions with red blood cells or platelets are allowed within 1 weekprior to screening assessment

• Leukocytes >= 3.0 K/cumm (within 14 days of enrollment)

• Absolute neutrophil count >= 1.5 K/cumm (within 14 days of enrollment)

• No administration of granulocyte colony-stimulating factor (G-CSF) is allowedwithin 1 week prior to screening assessment

• Platelets >= 100 K/cumm (within 14 days of enrollment)

• No transfusions with red blood cells or platelets are allowed within 1 weekprior to screening assessment

• Serum albumin >= 2.5 g/dL (within 14 days of enrollment)

• Total bilirubin =< 1.5 × institutional upper limit of normal (ULN), (< 3 × ULN inthe presence of documented Gilbert's syndrome or liver metastases at baseline) (within 14 days of enrollment)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN (if liver metastases are present =< 5 x ULN) (within 14 days ofenrollment)

• International normalized ratio (INR)/prothrombin time (PT) and activated partialthromboplastin time (aPTT) =< 1.5 x institutional ULN (within 14 days of enrollment)

• This applies only to patients who are not receiving therapeutic anticoagulationthat may affect INR. Those who are on therapeutic anticoagulation, should be ona stable dose for 4 weeks and should be considered within therapeutic range

• Creatinine =< 1.5 x institutional ULN OR Glomerular filtration rate (GFR) >= 30mL/min/1.73 m^2 (using the Cockcroft-Gault equation) (within 14 days of enrollment)

• Patients who are human immunodeficiency virus (HIV)-positive may participate IF theymeet the following eligibility requirements:

• They must be stable on their anti-retroviral regimen, and they must be healthyfrom an HIV perspective

• They must have a CD4 count of greater than 250 cells/mcL over the past 6 monthson this same anti-retroviral regimen and must not have had a CD4 count < 200cells/ul over the past 2 years, unless it was deemed related to THE CANCERAND/OR CHEMOTHERAPY-induced bone marrow suppression

• For patients who have received chemotherapy in the past 6 months, a CD4count < 250 cells/ul during chemotherapy is permitted as long as viralloads were undetectable during this same chemotherapy

• They must have an undetectable viral load and a CD4 count >= 250 cells/uLwithin 7 days of enrollment

• They must not be currently receiving prophylactic therapy for an opportunisticinfection and must not have had an opportunistic infection within the past 6months HIV-infected patients should be monitored every 12 weeks for viral loadand CD4 counts

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if the following criteria aremet: 1) follow-up brain imaging done at least in 4 weeks after central nervoussystem (CNS)-directed therapy shows no evidence of progression and 2) the patient nolonger requires steroids, or is on a stable steroid dose > 4 weeks

• Patients with radiographically new or progressive brain metastases (active brainmetastases) or leptomeningeal disease are eligible only if has no progressiveclinical symptoms and if the treating physician determines that immediate CNSspecific treatment is not required and is unlikely to be required during the firstcycle of therapy

• Patients should be New York Heart Association functional classification of class 2Bor better

• Patients must have left ventricular ejection fraction (LVEF) >= 50% by either anechocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days beforerandomization/enrollment

• Dose expansion phase (PD cohort): Patients must have disease that is evaluable ormeasurable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

• Dose expansion phase (PD cohort): Patients must have at least one lesion suitablefor biopsy without significant risk to the patient. The biopsiable lesion can be thesame as the evaluable lesion for response by RECIST 1.1

• HER2 antibody conjugated to a topoisomerase 1 inhibitor agents as well as othertherapeutic agents used in this trial are known to be teratogenic; thus, women ofchild-bearing potential and men must agree to use adequate contraception (hormonalor barrier method of birth control; abstinence) prior to study entry, for theduration of study participation, and for at least 1 month after the last dose ofneratinib, or at least 7 months after the last dose of DS-8201a, whichever is longer (women of childbearing potential [WOCBP] only). Should a woman become pregnant orsuspect she is pregnant while she or her partner is participating in this study, sheshould inform her treating physician immediately. Men treated or enrolled on thisprotocol must also agree to use adequate contraception prior to the study, for theduration of study participation, and 3 months after the last dose of neratinib, or 4months after completion of DS-8021a administration, whichever is longer

• Women of non-child-bearing potential defined as pre-menopausal females with adocumented tubal ligation or hysterectomy; or postmenopausal defined as 12 months ofspontaneous amenorrhea (in questionable cases, a blood sample with simultaneousfollicle-stimulating hormone [FSH] > 40 mIU/mL and estradiol < 40 pg/mL [< 147pmol/L] is confirmatory) are eligible. Females on hormone replacement therapy (HRT)and whose menopausal status is in doubt will be required to use one of thecontraception methods outlined for women of child-bearing potential if they wish tocontinue their HRT during the study. Otherwise, they must discontinue HRT to allowconfirmation of post-menopausal status prior to study enrollment. For most forms ofHRT, at least 2-4 weeks will elapse between the cessation of therapy and the blooddraw; this interval depends on the type and dosage of HRT. Following confirmation oftheir post-menopausal status, they can resume use of HRT during the study withoutuse of a contraceptive method

• Male subjects must not freeze or donate sperm starting at screening and throughoutthe study period, and at least 4 months after the final study drug administration.Preservation of sperm should be considered prior to enrollment in this study

• Female subjects must not donate, or retrieve for their own use, ova from the time ofscreening and throughout the study treatment period, and for at least 7 months afterthe final study drug administration

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity who have alegally-authorized representative (LAR) and/or family member available will also beeligible

Exclusion Criteria:

• With the exception of medications that are under investigation in the study (e.g.,standard of care, comparators, or combination therapies), the following medications,treatment, and procedures will be prohibited during the treatment period:

• Other anticancer therapy, including small-molecule targeted agents within 2weeks or five half-lives, whichever is longer; chemotherapy otherwise notspecified (including, but not limited to cytotoxic chemotherapy, antibody drugconjugates, retinoid therapy, hormonal therapy) within 3 weeks; immunotherapyor monoclonal antibody within 4 weeks; and nitrosureas or mitomycin C within 6weeks (concurrent use of hormones for noncancer-related conditions [e.g.,insulin for diabetes and hormone replacement therapy] is acceptable)

• Other investigational therapeutic agents

• Patients who have had major surgery or radiation within 4 weeks; palliativestereotactic radiation within 2 weeks (except for palliative radiation to knownmetastatic sites as long as it does not affect assessment of response orinterrupt treatment for more than the maximum time specified in dosemodification section)

• Radiotherapy to the thorax (palliative radiation to known metastatic sites inthe thoracic spine is permitted in this study)

• Concomitant use of chronic systemic (IV or oral) corticosteroids or otherimmunosuppressive medications except for managing adverse events (inhaledsteroids or intra-articular steroid injections are permitted in this study);chronic replacement dose steroids (e.g., for those with adrenal insufficiency)are permitted in this study

• Subjects with bronchopulmonary disorders who require intermittent use ofbronchodilators (such as albuterol) will not be excluded from this study

• Concomitant treatment with chloroquine or hydroxychloroquine is not allowedduring the study treatment due to concern for overlapping toxicities. Iftreatment with chloroquine and hydroxychloroquine treatment is absolutelyrequired, study treatment must be interrupted. If chloroquine orhydroxychloroquine is administered, then a wash-out period of more than 14 daysis required before restarting study treatment

• Receipt of live, attenuated vaccine (messenger ribonucleic acid [mRNA] andreplication deficient adenoviral vaccines are not considered attenuated livevaccines) within 30 days prior to the first dose of study drug

• Patients with a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or wheresuspected ILD/pneumonitis cannot be ruled out by imaging at screening

• Patients with clinically severe pulmonary compromise resulting from intercurrentpulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e. pulmonary emboli within three months of the study enrollment, severe asthma,severe chronic obstructive pulmonary disease (COPD), restrictive lung disease,pleural effusion, etc.), and any autoimmune, connective tissue or inflammatorydisorders with potential pulmonary involvement (i.e. rheumatoid arthritis,Sjogren's, sarcoidosis, etc.), or prior pneumonectomy

• Patients with history of allergic reactions attributed to compounds of similarchemical or biologic composition to DS-8201a, the inactive ingredients in the drugproduct, or neratinib

• Patients who have a history of severe hypersensitivity reactions to other monoclonalantibodies

• Patients receiving any medications or substances that are moderate or stronginhibitors or inducers of CYP3A4 and P-glycoprotein are ineligible. Avoidconcomitant use with proton pump inhibitors and P-glycoprotein substrates. Becausethe lists of these agents are constantly changing, it is important to regularlyconsult a frequently-updated medical reference. As part of the enrollment/informedconsent procedures, the patient will be counseled on the risk of interactions withother agents, and what to do if new medications need to be prescribed or if thepatient is considering a new over-the-counter medicine or herbal product

• Patients with a medical history of myocardial infarction within 6 months beforeenrollment, or symptomatic congestive heart failure (CHF) (New York HeartAssociation class II to IV)

• Patients with a corrected QT interval (QTc) prolongation to > 470 ms (females) or > 450 ms (males) based on average of the screening triplicate 12-leadelectrocardiogram (ECG)

• Patients with clinically significant corneal disease in the opinion of theinvestigator

• Patients with a pleural effusion, ascites, or pericardial effusion that requiresdrainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy (CART). (Drainage and CART are not allowed within 2 weeks prior to screeningassessment) (GC indication)

• Patients with spinal cord compression

• Patients with an uncontrolled infection requiring IV antibiotics, antivirals, orantifungals

• Patients with unresolved toxicities from previous anticancer therapy, defined astoxicities (other than alopecia) not yet resolved to grade =< 1 or baseline.Subjects with chronic grade 2 toxicities may be eligible per the discretion of theinvestigator after consultation with the sponsor medical monitor or designee (e.g.,grade 2 chemotherapy-induced neuropathy)

• Patients with substance abuse or any other medical conditions such as clinicallysignificant cardiac or psychological conditions, that may, in the opinion of theinvestigator, interfere with the subject's participation in the clinical study orevaluation of the clinical study results

• Pregnant women are excluded from this study because DS-8201a is a HER2 antibodyconjugated to a topoisomerase 1 inhibitor agent with the potential for teratogenicor abortifacient effects. Because there is an unknown but potential risk for adverseevents in nursing infants secondary to treatment of the mother with DS-8201a,breastfeeding should be discontinued if the mother is treated with DS-8201a. Thesepotential risks may also apply to other agents used in this study

• Prior treatment with neratinib or DS-8201a

• Clinically significant chronic gastrointestinal disorder with diarrhea as a majorsymptom; G2 or greater diarrhea at baseline. Please contact the study PI for anypatient with more than two episodes of diarrhea per day averaged over at least a 7day period at time of screening to determine whether the diarrhea would beconsidered clinically significant

• Inability to swallow tablets

• Patients with active additional malignancy or a personal history of additionalmalignancy that may affect outcome of disease under treatment (patients with a prioror concurrent malignancy whose natural history or treatment does not have thepotential to interfere with the safety or efficacy assessment of the investigationalregimen at the discretion of the treating investigator are allowed)

• Patients with prior allogeneic organ transplantation including allogeneic stem celltransplantation