Testing the Combination of Two Anti-cancer Drugs, DS-8201a and AZD6738, for The Treatment of Patients With Advanced Solid Tumors Expressing the HER2 Protein or Gene, The DASH Trial
Testing the Combination of Two Anti-cancer Drugs, DS-8201a and AZD6738, for The Treatment of Patients With Advanced Solid Tumors Expressing the HER2 Protein or Gene, The DASH Trial
The dose escalation phase of this trial identifies the best dose and safety of AZD6738 when
 given in combination with DS-8201a in treating patients with solid tumors that have a change
 (mutation) in the HER2 gene or protein and have spread to other places in the body
 (advanced). The dose expansion phase (phase Ib) of this trial compares how colorectal and
 gastroesophageal cancers with HER2 mutation respond to treatment with a combination of
 AZD6738 and DS-8201a versus DS-8201a alone. Trastuzumab deruxtecan (DS-8201a) is a monoclonal
 antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab
 attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill
 them. AZD6738 may stop the growth of tumor cells by blocking some of the enzymes needed for
 cell growth.
PRIMARY OBJECTIVES:

 I. Evaluate safety, tolerability and recommended phase 2 dose (RP2D) of trastuzumab
 deruxtecan (DS-8201a) in combination with ceralasertib (AZD6738) in advanced solid tumors
 with HER2 expression. (Escalation Phase) II. Assess differential pharmacodynamic (PD) profile
 of tumor tissue (deoxyribonucleic acid [DNA] damage & repair) between Top1 inhibition and
 dual inhibition of Top1 and ATR in patients with colorectal cancer and gastroesophageal
 cancer with HER2 expression. (Expansion Phase)

 SECONDARY OBJECTIVES:

 I. To observe and record anti-tumor activity. II. To evaluate pharmacokinetics (PK) of
 DS-8201a and AZD6738 and immunogenicity of DS8201a.

 EXPLORATORY OBJECTIVES:

 I. Evaluate association between HER2 heterogeneity and response to DS-8201a plus (+) AZD6738
 therapy using central protein expression assessment.

 II. Determine predictive biomarkers (including but not restricted to: HER2 protein levels,
 HER2 gene copy number, alterations of TP53, ATM and RAS) of DS-8201a + AZD6738 efficacy in
 advanced solid tumors (specifically colorectal cancer and gastroesophageal cancer) with HER2
 expression III. To characterize PD biomarkers for efficacy of DS-8201a + AZD6738 efficacy in
 advanced solid tumors (specifically colorectal cancer and gastroesophageal cancer) with HER2
 expression (such as pRAD50 and SLFN11).

 IV. To establish a biorepository of tissue, blood and pre-clinical models (PDXs) for HER2
 expressing advanced solid tumors (specifically colorectal cancer and gastroesophageal
 cancer).

 OUTLINE: This is a dose-escalation study of AZD6738 with fixed dose DS-8201a followed by a
 dose-expansion study.

 Patients receive trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1 and
 ceralasertib orally (PO) twice daily (BID) on days 1-7. Cycles repeat every 21 days in the
 absence of disease progression or unacceptable toxicity. NOTE: During the dose-expansion
 phase, the first 6 patients in each disease cohort (gastroesophageal cancer [cohort A] and
 colorectal cancer [cohort B]) receive only DS-8201a for the first cycle, followed by DS-8201
 and AZD6738 together in subsequent cycles.

 After completion of study treatment, patients are followed up every 3 months for 2 years,
 then every 6 months for 3 years.
Inclusion Criteria:

 -  DOSE-ESCALATION PHASE: Must have histologically confirmed advanced solid tumor

 -  DOSE-EXPANSION PHASE: Must have histologically confirmed advanced/metastatic
 gastroesophageal cancer (cohort A) or colorectal cancer (cohort B)

 -  DOSE-EXPANSION PHASE: Patients must have a biopsiable lesion and provide consent for
 on treatment biopsy

 -  Age >=18 years. Because no dosing or adverse event data are currently available on the
 use of AZD6738 in combination with DS-8201a in patients < 18 years of age, children
 are excluded from this study

 -  Patients must have HER2-positive or HER2-expressing tumors determined by a Clinical
 Laboratory Improvement Act (CLIA)-certified laboratory. As a rule, for HER2
 immunohistochemistry (IHC) scoring system trastuzumab for gastric cancer (TOGA)
 criteria used for gastric/gastroesophageal junction (GEJ) cancers will be employed
 (Note: in escalation phase, for breast cancer patients that are included, breast
 cancer criteria can be used). Specific requirement of HER2 status is outlined below:

 -  HER2 expression (1-3+) by IHC locally and confirmed centrally OR

 -  HER2 expression (1-3+) by IHC tested centrally OR

 -  HER2 amplification based on fluorescence in situ hybridization (FISH) or next
 generation sequencing

 -  Must have received at least one line of systemic chemotherapy for either locally
 advanced or metastatic disease and should have either progressed on this therapy or
 been intolerant to this therapy

 -  For tumors where anti-HER2 therapy is standard of care, patients must have progressed
 on at least 1 line of anti-HER2 therapy if eligible

 -  Must have unresectable, advanced/metastatic disease

 -  Must have at least 1 measurable lesion on computed tomography (CT) scan per Response
 Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patient without measurable but
 evaluable disease are allowed for dose-escalation phase

 -  Must be willing and able to provide an adequate archival tumor sample available to
 confirm HER2 status by Central Laboratory (if local testing is used for enrollment),
 else must be willing and able to provide an adequate archival tumor sample for HER2
 testing centrally

 -  Must have Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

 -  Must have life expectancy of at least 3 months

 -  Must have left ventricular ejection fraction (LVEF) >= 50% within 28 days before
 enrollment (study drug treatment) by either an echocardiogram (ECHO) or multigated
 acquisition (MUGA) scan

 -  Must have a negative pregnancy test (if female)

 -  Platelets >= 100,000/mcL (within 14 days before enrollment)

 -  No transfusions with red blood cells or platelets are allowed within 1 week prior
 to screening assessment

 -  Hemoglobin >= 9.0 g/dL (within 14 days before enrollment)

 -  Absolute neutrophil count >= 1,500/mcL (within 14 days before enrollment)

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

 -  Creatinine clearance > 45/mL/min (using the Cockcroft-Gault equation) (within 14 days
 before enrollment)

 -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
 =< 5 x institutional upper limit of normal (ULN) (within 14 days before enrollment)

 -  Total bilirubin =< 1.5 x ULN if no liver metastases or < 3 x ULN with Gilbert's
 Syndrome or liver metastases at baseline (within 14 days before enrollment)

 -  Leukocytes >= 3,000/mcL (within 14 days before enrollment)

 -  Albumin > 2.5 g/dL (GEJ patients only) (within 14 days before enrollment)

 -  International normalized ratio (INR) and either partial thromboplastin time (PTT) or
 activated (a)PTT =< 1.5 x ULN (within 14 days before enrollment)

 -  Must have adequate treatment washout period before study treatment, defined as: Major
 surgery (>= 4 weeks), radiation therapy (>= 3 weeks; in case of palliative radiation
 >= 2 weeks), systemic therapy (>= 3 weeks; in case of investigational drug use >= 2
 weeks or 5 half-lives, whichever is longer)

 -  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/mcl 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/mcl 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/mcL 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

 -  Subjects with clinically inactive brain metastases may be included. Subjects with
 treated brain metastases that are no longer symptomatic and who require no treatment
 with corticosteroids or anticonvulsants may be included in the study if they have
 recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have
 elapsed between the end of whole-brain radiation therapy and study treatment

 -  Patients with new or progressive brain metastases (active brain metastases) or
 leptomeningeal disease are eligible if the treating physician determines that
 immediate central nervous system (CNS) specific treatment is not required and is
 unlikely to be required for at least 4 weeks (or scheduled assessment after the first
 cycle of treatment), and a risk-benefit analysis (discussion) by the patient and the
 investigator favors participation in the clinical trial

 -  Patients with a prior or concurrent malignancy whose natural history or treatment does
 not have the potential to interfere with the safety or efficacy assessment of the
 investigational regimen are eligible for this trial

 -  HER2 antibody conjugated to a topoisomerase 1 inhibitor agents as well as AZD6738 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 7
 months (women of childbearing potential [WOCBP] only) after the last dose of study
 drug. 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 6
 months after completion of study drug administration

 -  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 6 months after the final study drug administration.
 Preservation of sperm should be considered prior to enrolment 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 (IDMC) who have a
 legally-authorized representative (LAR) and/or family member available will also be
 eligible

 Exclusion Criteria:

 -  Patients with a history of (non-infectious) interstitial lung disease
 (ILD)/pneumonitis that required steroids, have current ILD/pneumonitis, or where
 suspected ILD/pneumonitis cannot be ruled out by imaging at screening. Patient using
 e-cigarettes/vaping are also excluded

 -  Patients with a medical history of myocardial infarction within 6 months before
 enrollment (study treatment), symptomatic congestive heart failure (New York Heart
 Association Class II to IV, corrected QT interval (QTcF) prolongation to > 470 ms
 (females) or > 450 ms (males) as corrected by Framingham's formula

 -  Patients with spinal cord compression or clinically active central nervous system
 metastases, defined as untreated and symptomatic, or requiring therapy with
 corticosteroids or anticonvulsants to control associated symptoms

 -  Patients with multiple primary malignancies within 2 years, except adequately resected
 non-melanoma skin cancer, curatively treated in situ disease, or other curatively
 treated solid tumors

 -  Patients with a history of severe hypersensitivity reactions to either the drug
 substances or inactive ingredients in the drug product

 -  Patients with an uncontrolled infection requiring IV antibiotics, antivirals, or
 antifungals

 -  Patients with substance abuse or any other medical conditions that would increase the
 safety risk to the subject or interfere with participation of the subject or
 evaluation of the clinical study in the opinion of the investigator

 -  Patients with a concomitant medical condition that would increase the risk of toxicity
 in the opinion of the investigator

 -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
 (i.e., have residual toxicities grade >1) with the exception of alopecia. Subjects
 with chronic grade 2 toxicities may be eligible per discretion of the investigator
 after discussion with study principal investigator (PI) (e.g., grade 2 chemo-induced
 neuropathy).

 -  Any previous treatment with an ATR inhibitor

 -  Patients with any clinically apparent pulmonary compromise resulting from intercurrent
 pulmonary 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 inflammatory disorders with
 potential pulmonary involvement (i.e., Rheumatoid arthritis, Sjogren's, sarcoidosis,
 etc.), or prior pneumonectomy

 -  Patients with myelodysplastic syndrome/acute myeloid leukemia or with features
 suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)

 -  Patients unable to swallow orally administered medication and patients with
 gastrointestinal disorders likely to interfere with absorption of the study medication

 -  Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin,
 clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
 saquinavir, nelfinavir, boceprevir, telaprevir). The required washout period prior to
 starting study treatment is 2 weeks. Concomitant use of known strong (e.g.,
 phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine,
 carbamazepine, nevirapine and St John's Wort ). The required washout period prior to
 starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for
 other agents

 -  Patients with a pleural effusion, ascites, or pericardial effusion that requires
 drainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy
 (CART). (Drainage and CART are not allowed within 2 weeks prior to screening
 assessment)

 -  Patients with previous allogeneic bone marrow transplant or double umbilical cord
 blood transplantation (dUCBT)

 -  Whole blood transfusions in the last 120 days prior to entry to the study (packed red
 blood cells and platelet transfusions are acceptable within the last 28 days as long
 as they are not within 1 week prior to screening assessment)

 -  Patients at risk of brain perfusion problems, e.g., medical history of carotid
 stenosis or pre-syncopal or syncopal episodes, history of transient ischemic attacks
 (TIAs)

 -  Uncontrolled hypertension (grade 2 or above) requiring clinical intervention

 -  Patients with relative hypotension (<90/60 mm Hg) or clinically relevant orthostatic
 hypotension, including a fall in blood pressure of > 20 mm Hg

 -  Patients who have received corticosteroids (at a dose > 10 mg prednisone/day or
 equivalent) for any reason within 2 weeks prior to first dose

 -  Patients with uncontrolled intercurrent illness

 -  Patients with psychiatric illness/social situations that would limit compliance with
 study requirements

 -  Pregnant women are excluded from this study because DS-8201a is a HER2 antibody
 conjugated to a topoisomerase 1 inhibitor agent with the potential for teratogenic or
 abortifacient effects. Because there is an unknown but potential risk for adverse
 events in nursing infants secondary to treatment of the mother with DS-8201a,
 breastfeeding should be discontinued if the mother is treated with DS-8201a. These
 potential risks may also apply to AZD6738

 -  Patients cannot be receiving chloroquine or hydroxychloroquine. Patients receiving
 these drugs must have a washout period of > 14 days before enrollment/randomization