Pancreatic Cancer Clinical Trials

• Patients must have histologically confirmed malignancy that is metastatic or unresectable with participation in this clinical trial determined to be the best option for next treatment in the opinion of the investigator, and meet the following specific criteria:

‣ Patients enrolling in Part 1 (Dose Escalation) may have a diagnosis of any solid tumor

⁃ Patients enrolling in the Part 2 Pharmacodynamic Cohort may have a diagnosis of any solid tumor except pancreas cancer (NOTE: pancreatic cancer excluded from this cohort after Revision 11 activation due to the addition of the pancreatic specific cohort)

⁃ Patients enrolling in the Part 2 Pancreatic Cohort must have a diagnosis of pancreatic adenocarcinoma (PDAC) and meet the HER2 positivity guidance

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

‣ HER2 overexpression defined by immunohistochemistry (IHC) 3+

⁃ ERBB2 amplification by in situ hybridization (ISH) or next-generation sequencing as determined by any Clinical Laboratory Improvement Act (CLIA) certified lab

⁃ A known HER2 activating mutation

⁃ HER2 overexpression by IHC/ISH will follow histology specific American Society of Clinical Oncology (ASCO)-College of American Pathologists (CAP) guidelines for breast and gastric cancers. HER2 overexpression by IHC/ISH for the Pancreatic Cohort will follow ASCO-CAP guidelines for gastric cancers. For tumor histologies without specific guidelines the following criteria will apply:

• HER2 IHC should be performed first, followed by ISH methods in cases showing 2+ (equivocal) expression by IHC. Positive (IHC 3+) or negative (IHC 0 or 1+) do not require further ISH testing. Cases with HER2:CEP17 ratio ≥ 2 or an average HER2 copy number ≥ 6.0 signals per cell are considered 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 the advanced/metastatic setting. No limitation on number of prior therapies; however, patients may not have received neratinib or DS-8201a previously. Prior HER2-targeted therapy 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 on the 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 of enrollment)

‣ No transfusions with red blood cells or platelets are allowed within 1 week prior 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 allowed within 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 week prior 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 in the 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 of enrollment)

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

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

• Creatinine =\< 1.5 x institutional ULN OR Glomerular filtration rate (GFR) \>= 30 mL/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 they meet the following eligibility requirements:

‣ They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective

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

• For patients who have received chemotherapy in the past 6 months, a CD4 count \< 250 cells/ul during chemotherapy is permitted as long as viral loads were undetectable during this same chemotherapy

⁃ They must have an undetectable viral load and a CD4 count \>= 250 cells/uL within 7 days of enrollment

⁃ They must not be currently receiving prophylactic therapy for an opportunistic infection and must not have had an opportunistic infection within the past 6 months.

∙ HIV-infected patients should be monitored every 12 weeks for viral load and CD4 counts

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

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

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

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

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

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

• Part 2, Pancreatic cohort ONLY: Patients must have disease that is measurable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

• Part 2, PD cohort ONLY: Patients must have disease that is evaluable or measurable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

• Part 2, PD cohort ONLY: Patients must have at least one lesion suitable for biopsy without significant risk to the patient. The biopsiable lesion can be the same as the evaluable lesion for response by RECIST 1.1

• HER2 antibody conjugated to a topoisomerase 1 inhibitor agents as well as other therapeutic agents used in this trial are known to be teratogenic; thus, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 1 month after the last dose of neratinib, 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 or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after the last dose of neratinib, or 4 months after completion of DS-8021a administration, whichever is longer

• Women of non-child-bearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating hormone \[FSH\] \> 40 mIU/mL and estradiol \< 40 pg/mL \[\< 147 pmol/L\] is confirmatory) are eligible. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for women of child-bearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method

• Male subjects must not freeze or donate sperm starting at screening and throughout the 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 of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration

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