A Precision Medicine Approach (SMMART-ACT) For The Treatment Of Patients With Advanced Sarcoma, Prostate, Breast, Ovarian Or Pancreatic Cancer

Study Overview

A Precision Medicine Approach (SMMART-ACT) for the Treatment of Patients With Advanced Sarcoma, Prostate, Breast, Ovarian or Pancreatic Cancer

This phase II trial tests the how well a precision medicine approach (serial measurements of molecular and architectural response to therapy [SMMART])-adaptive clinical treatment [ACT]) works in treating patients with sarcoma, prostate, breast, ovarian or pancreatic cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). SMMART testing uses genetic and protein tests to learn how cancer changes and to understand what drugs may work against a person's cancer or why drugs stop working. These test results are reviewed by a group of physicians and scientists during a SMMART tumor board who then recommend precision therapy.

PRIMARY OBJECTIVE: I. Feasibility of utilizing a SMMART-adaptive clinical treatment (ACT) tumor board to select personalized advanced cancer treatment plans based on a pre-determined set of drug agents with recommended phase 2 doses (RP2Ds). SECONDARY OBJECTIVES: I. Safety and tolerability of assigned ACT intervention per cancer type. II. Preliminary indications of efficacy based on disease-specific responses. III. Estimated survival benefit per cancer type. EXPLORATORY OBJECTIVES: I. Durability of response compared to the most recent therapy on which progression occurred. II. Changes in ability to conduct activities of daily living (ADL). III. Changes in quality of life (QoL). IV. Feasibility of SMMART-centric assessments of ongoing responses to treatment to identify mechanisms of therapy induced change, per investigator discretion. Such mechanisms may include, but will not be limited to, the following: IVa. Changes in tumor and tumor ecosystem biology; IVb. Response and resistance to therapy. OUTLINE: Patients are assigned to 1 of 14 arms. Participants may re-enter the study and receive a new arm assignment in the event of progressive disease or unacceptable toxicity. ARM I: Patients receive abemaciclib orally (PO) twice per day (BID) on days 1-21 and gemcitabine intravenously (IV) over 30 minutes on days 1 and 8 of each cycle. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. ARM II: Patients receive abemaciclib PO BID on days 1-21 and pemetrexed IV over 10 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. ARM III: Patients receive abemaciclib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. ARM IV: Patients receive abemaciclib PO BID and exemestane PO once per day (QD) on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. ARM V: Patients receive abemaciclib PO BID and letrozole PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. ARM VI: Patients receive abemaciclib PO BID and tamoxifen PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. ARM VII: Patients receive gefitinib PO QD on days 1-21, pemetrexed IV on day 1 of each cycle and carboplatin IV on day 1 of cycles 1-6. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. ARM VIII: Patients receive olaparib PO BID and temozolomide PO QD on days 1-7 of each cycle. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. ARM IX: Patients receive fulvestrant intramuscularly (IM) on days 1, 15 and 29 of cycle 1 and day 1 of subsequent cycles. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. ARM X: Patients receive gefitinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. ARM XI: Patients receive olaparib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy, CT scan, MRI scan, PET scan and/or bone scan and blood sample collection throughout the study. Additionally, prostate cancer patients undergo bone scan on study. ARM XII: Patients receive olaparib PO BID on days 1-3, 8-10, 15-17, 21-23 and carboplatin IV and paclitaxel IV on days 1, 8 and 15 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study, as clinically indicated, and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. ARM XIII: Patients receive olaparib PO BID on days 1-28 and liposomal doxorubicin IV on day 1 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography or multigated acquisition (MUGA) scan and blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. ARM XIV: Patients receive osimertinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography or MUGA scan and blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. After completion of study treatment, patients are followed up 30 days, every 3 months for 1 year then every 6 months until year 5.

Advanced Breast Carcinoma
Advanced Malignant Solid Neoplasm
Advanced Ovarian Carcinoma
Advanced Pancreatic Carcinoma
Advanced Prostate Carcinoma
Advanced Sarcoma
Anatomic Stage III Breast Cancer AJCC v8
Anatomic Stage IV Breast Cancer AJCC v8
Stage III Ovarian Cancer AJCC v8
Stage III Pancreatic Cancer AJCC v8
Stage III Prostate Cancer AJCC v8
Stage IV Ovarian Cancer AJCC v8
Stage IV Pancreatic Cancer AJCC v8
Stage IV Prostate Cancer AJCC v8

DRUG: Abemaciclib
PROCEDURE: Biopsy
PROCEDURE: Bone Scan
DRUG: Carboplatin
PROCEDURE: Echocardiography
DRUG: Exemestane
DRUG: Fulvestrant
DRUG: Gefitinib
DRUG: Gemcitabine
DRUG: Letrozole
PROCEDURE: Multigated Acquisition Scan
DRUG: Olaparib
DRUG: Osimertinib
DRUG: Paclitaxel
DRUG: Pegylated Liposomal Doxorubicin Hydrochloride
DRUG: Pemetrexed
OTHER: Survey Administration
DRUG: Tamoxifen
DRUG: Temozolomide
PROCEDURE: Biospecimen Collection

STUDY00026643
NCI-2024-07664 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
STUDY00026643 (OTHER Identifier) (OTHER: OHSU Knight Cancer Institute)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2024-09-26	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2025-06-26
First Submitted that Met QC Criteria 2024-10-04	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2025-06-29
First Posted (ACTUAL) 2024-10-08	Results First Posted N/A	Last Verified 2025-06

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Arm I (abemaciclib, gemcitabine) Patients receive abemaciclib PO BID on days 1-21 and gemcitabine IV over 30 minutes on days 1 and 8 of each cycle. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample	DRUG: Abemaciclib Given PO PROCEDURE: Biopsy Undergo tumor biopsy PROCEDURE: Bone Scan Undergo bone scan DRUG: Gemcitabine Given IV OTHER: Survey Administration Ancillary studies PROCEDURE: Biospecimen Collection Biological Sample Collection, Biological Sample Collection, Biospecimen Collected, Biospecimen Collection, Specimen Collection
EXPERIMENTAL: Arm II (abemaciclib, pemetrexed) Patients receive abemaciclib PO BID on days 1-21 and pemetrexed IV over 10 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collect	DRUG: Abemaciclib Given PO PROCEDURE: Biopsy Undergo tumor biopsy PROCEDURE: Bone Scan Undergo bone scan DRUG: Pemetrexed Given IV OTHER: Survey Administration Ancillary studies PROCEDURE: Biospecimen Collection Biological Sample Collection, Biological Sample Collection, Biospecimen Collected, Biospecimen Collection, Specimen Collection
EXPERIMENTAL: Arm III (abemaciclib) Patients receive abemaciclib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also und	DRUG: Abemaciclib Given PO PROCEDURE: Biopsy Undergo tumor biopsy PROCEDURE: Bone Scan Undergo bone scan OTHER: Survey Administration Ancillary studies PROCEDURE: Biospecimen Collection Biological Sample Collection, Biological Sample Collection, Biospecimen Collected, Biospecimen Collection, Specimen Collection
EXPERIMENTAL: Arm IV (abemaciclib, exemestane) Patients receive abemaciclib PO BID and exemestane PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the stu	DRUG: Abemaciclib Given PO PROCEDURE: Biopsy Undergo tumor biopsy PROCEDURE: Bone Scan Undergo bone scan DRUG: Exemestane Given PO OTHER: Survey Administration Ancillary studies PROCEDURE: Biospecimen Collection Biological Sample Collection, Biological Sample Collection, Biospecimen Collected, Biospecimen Collection, Specimen Collection
EXPERIMENTAL: Arm V (abemaciclib, letrozole) Patients receive abemaciclib PO BID and letrozole PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the stud	DRUG: Abemaciclib Given PO PROCEDURE: Biopsy Undergo tumor biopsy PROCEDURE: Bone Scan Undergo bone scan DRUG: Letrozole Given PO OTHER: Survey Administration Ancillary studies PROCEDURE: Biospecimen Collection Biological Sample Collection, Biological Sample Collection, Biospecimen Collected, Biospecimen Collection, Specimen Collection
EXPERIMENTAL: Arm VI (abemaciclib, tamoxifen) Patients receive abemaciclib PO BID and tamoxifen PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the stud	DRUG: Abemaciclib Given PO PROCEDURE: Biopsy Undergo tumor biopsy PROCEDURE: Bone Scan Undergo bone scan OTHER: Survey Administration Ancillary studies DRUG: Tamoxifen Given PO PROCEDURE: Biospecimen Collection Biological Sample Collection, Biological Sample Collection, Biospecimen Collected, Biospecimen Collection, Specimen Collection
EXPERIMENTAL: Arm VII (gefitinib, pemetrexed, carboplatin) Patients receive gefitinib PO QD on days 1-21, pemetrexed IV on day 1 of each cycle and carboplatin IV on day 1 of cycles 1-6. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo	PROCEDURE: Biopsy Undergo tumor biopsy PROCEDURE: Bone Scan Undergo bone scan DRUG: Carboplatin Given IV DRUG: Gefitinib Given PO DRUG: Pemetrexed Given IV OTHER: Survey Administration Ancillary studies PROCEDURE: Biospecimen Collection Biological Sample Collection, Biological Sample Collection, Biospecimen Collected, Biospecimen Collection, Specimen Collection
EXPERIMENTAL: Arm VIII (olaparib, temozolomide) Patients receive olaparib PO BID and temozolomide PO QD on days 1-7 of each cycle. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study	DRUG: Olaparib Given PO DRUG: Temozolomide Given PO
EXPERIMENTAL: Arm IX (fulvestrant) Patients receive fulvestrant IM on days 1, 15 and 29 of cycle 1 and day 1 of subsequent cycles. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection through	PROCEDURE: Biopsy Undergo tumor biopsy DRUG: Fulvestrant Given IM OTHER: Survey Administration Ancillary studies PROCEDURE: Biospecimen Collection Biological Sample Collection, Biological Sample Collection, Biospecimen Collected, Biospecimen Collection, Specimen Collection
EXPERIMENTAL: Arm X (gefitinib) Patients receive gefitinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also underg	DRUG: Gefitinib Given PO
EXPERIMENTAL: Arm XI (olaparib) Patients receive olaparib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also underg	DRUG: Olaparib Given PO
EXPERIMENTAL: Arm XII (olaparib, carboplatin, paclitaxel) Patients receive olaparib PO BID on days 1-3, 8-10, 15-17, 21-23 and carboplatin IV and paclitaxel IV on days 1, 8 and 15 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patient	DRUG: Carboplatin Given IV DRUG: Olaparib Given PO DRUG: Paclitaxel Given IV
EXPERIMENTAL: Arm XIII (olaparib, liposomal doxorubicin) Patients receive olaparib PO BID on days 1-28 and liposomal doxorubicin IV on day 1 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography or MUGA sca	PROCEDURE: Echocardiography Undergo echocardiography PROCEDURE: Multigated Acquisition Scan Undergo MUGA DRUG: Olaparib Given PO DRUG: Pegylated Liposomal Doxorubicin Hydrochloride Given IV
EXPERIMENTAL: Arm XIV (osimertinib) Patients receive osimertinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography or MUGA scan and blood sample collection throug	PROCEDURE: Echocardiography Undergo echocardiography PROCEDURE: Multigated Acquisition Scan Undergo MUGA DRUG: Osimertinib Given PO

Primary Outcome Measures	Measure Description	Time Frame
Proportion of participants who receive an adaptive clinical treatment (ACT) therapy based serial measurements of molecular and architectural responses to therapy (SMMART)-ACT tumor board recommendation	A threshold of the posterior probability rate of 75% will be utilized for declaring feasibility to support the analysis of the primary objective in this pilot.	From SMMART-ACT tumor board review to the first dose of ACT study drug per unique treatment regimen. This is expected to take up to approximately 30 days.

Secondary Outcome Measures	Measure Description	Time Frame
Incidence of treatment emergent adverse events (TEAEs) suspected or confirmed as attributed to study therapy	The incidence of TEAEs experienced that are suspected or confirmed as attributable to a study drug or procedure will be tabulated	From first dose of study drug to 30 days after last dose of study drug(s). This is expected to be approximately 7 months, but could be shorter if participant stops treatment early for any reason.
Rate of treatment discontinuation due to toxicities and/or intolerability	The incidence of discontinuation from study therapy due to intolerability and/or toxicities will be reported.	From first dose of study drug to last dose of study drug(s). This is expected to be approximately 6 months, but could be shorter if participant stops treatment early for any reason.
Overall response rate (ORR)	ORR is defined as complete response + partial response. Will be assessed per Response Evaluation Criteria in Solid Tumors (RECIST). An exact 95% confidence interval will be provided.	At 24 weeks from cycle 1 day 1
Progression free survival	Will be estimated using the Kaplan-Meier method.	From first dose of study drug to first date of documented progression or recurrence (RECIST 1.1), end-of-study, or death due to any cause, whichever occurs first, up to 5 years
Disease specific survival (DSS)	Will be estimated using the Kaplan-Meier method. Analysis will also fit DSS and subdistribution hazard models for both DSS death and non-DSS death.	From first dose of study drug to death as a result of the disease, up to 5 years
Overall survival	Will be summarized descriptively using the Kaplan-Meier method. The median and 95% confidence interval will be included in the estimations, if possible.	From first dose of study drug to date of death from any cause, up to 5 years

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Name: Knight Cancer Institute Clinical Trials Information

Phone Number: 503-494-1080

Email: trials@ohsu.edu

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

PRE-SCREENING: Written informed consent prior to any Pre-Screening activities, study-specific procedures or interventions
PRE-SCREENING: At least 18 years of age at time of informed consent. Persons of all gender identities, biological sexes, races, and ethnicities will be included
PRE-SCREENING: A diagnosis of advanced sarcoma or advanced prostate, breast, ovarian, or pancreatic cancer. Change in an individual's cancer can be tracked objectively according to the Prostate Cancer Working Group 3 (PCWG3) criteria for prostate cancer, and Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria for sarcomas and breast, ovarian, and pancreatic cancers
PRE-SCREENING: Biospecimen collection, as per institutional standards, must be consented to and collection must be feasible, with the following exceptions for tissue collections:

Individuals with a prior tumor tissue sample with successful SMMART-Clinical Analytics Platform (CAP) assays, collected within the last 90 days, may be eligible, so long as ≤ 1 treatment has been received within ≤ 90 days of that biopsy
PRE-SCREENING: Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
PRE-SCREENING: Physician-assessed life expectancy of ≥ 6 months
PRE-SCREENING: Additional eligibility criteria specific to their disease must also be met
PRIMARY TREATMENT: Documented progression after at least 1 line of prior therapy for advanced disease. If recurrence occurred within 6 months of the last dose of an adjuvant/neoadjuvant therapy, that adjuvant/neoadjuvant therapy will count as 1 line of therapy
PRIMARY TREATMENT: SMMART-ACT tumor board recommendation of at least one SMMART-ACT therapy regimen defined within this protocol, based on the board's review of SMMART-CAP results on a pre-screening biopsy
PRIMARY TREATMENT: Absolute neutrophil count (ANC) ≥ 1,500/uL (1.5 K/cu mm) (assessed at primary [post pre-screening] screening, or by the time that study intervention commences)
PRIMARY TREATMENT: Platelets ≥ 100,000/uL (100 K/cu mm) (assessed at primary [post pre-screening] screening, or by the time that study intervention commences)
PRIMARY TREATMENT: Hemoglobin ≥ 9 g/dL (or ≥ 5.6 mmol/L) (assessed at primary [post pre-screening] screening, or by the time that study intervention commences)
PRIMARY TREATMENT: Creatinine OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) ≤ 1.5 x institutional upper limit of normal (ULN) (institutional upper limit of normal [IULN]) OR ≥ 50 mL/min/1.73 m^2 (assessed at primary [post pre-screening] screening, or by the time that study intervention commences)

Creatinine clearance should be calculated per institutional standard. For participants with a baseline calculated creatinine clearance below normal institutional laboratory values, a measured baseline creatinine clearance should be determined. Individuals with higher values felt to be consistent with inborn errors of metabolism will be considered on a case-by-case basis.
Creatinine clearance of > 30 mL/min may be considered given that renal toxicity is not at increased risk and excretion is not major route of clearance for any chosen SMMART-ACT therapeutic
PRIMARY TREATMENT: Total bilirubin ≤ 1.5 x IULN OR direct bilirubin ≤ IULN for individuals with total bilirubin levels > 1.5 x IULN (assessed at primary [post pre-screening] screening, or by the time that study intervention commences)
PRIMARY TREATMENT: Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x IULN (assessed at primary [post pre-screening] screening, or by the time that study intervention commences)
PRIMARY TREATMENT: International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN, unless individual is receiving anticoagulant therapy, as long as PT or partial thromboplastin time (PTT) is within intended therapeutic range of intended anticoagulant therapy (assessed at primary [post pre-screening] screening, or by the time that study intervention commences)
PRIMARY TREATMENT: Activated partial thromboplastin time (aPTT) or PTT ≤ 1.5 x ULN, unless participant is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended anticoagulant therapy (assessed at primary [post pre-screening] screening, or by the time that study intervention commences)
PRIMARY TREATMENT: Body mass index (BMI) > 16.0 and < 35.0 kg/m^2 (assessed at primary [post pre-screening] screening, or by the time that study intervention commences)

Participants with a BMI of ≥ 30.0 will use ideal body weight indices in calculating the delivery of agents that are dosed based upon body surface area (i.e., mg agent/meter squared) or weight (i.e., mg agent/kg body weight)
PRIMARY TREATMENT: Toxicities due to prior therapies should be resolved to baseline or grade 1 (per Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5.0) before administration of study intervention. The following exceptions are permitted:

Alopecia, fatigue, and lymphopenia due to prior therapies.
Toxicities attributed to prior anti-cancer therapy that are not expected to resolve and to result in long lasting sequelae (e.g., neuropathy after platinum-based therapy), may be permitted
PRIMARY TREATMENT: Palliative radiation therapy completed ≥ two weeks prior to start of SMMART-ACT treatment to a measurable disease lesion(s)
PRIMARY TREATMENT: Study intervention-specific eligibility criteria for the intended, recommended therapy must also be met
CANCER-SPECIFIC CRITERIA (BREAST CANCER): Lesion(s) remain measurable after systemic therapies, as follows:

At least one prior line of pharmacological therapy for hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2)-negative disease.
At least one prior line of targeted therapy for HER2-positive disease
At least one prior line of combination therapy for triple negative disease lacking a BRCA1/2 mutation.
At least one prior line of therapy with a PARP inhibitor for triple negative disease with a BRCA1/2 mutation

PRE-SCREENING: Evidence of active malignancy of another cancer with a natural history or treatment history that may affect safety or efficacy assessments of this study or impose unacceptable risk to the participant. Guiding examples for those who can be enrolled include: individuals who have been disease free for ≥ two years; cancers with high cure rates (e.g., prior history of stage 1 rectal cancer and currently otherwise disease free); adequately treated, localized nonmelanomatous skin cancer
PRE-SCREENING: Absence of biopsiable lesion, AND unavailable/insufficient archival tissue
PRIMARY TREATMENT: Any brain/central nervous system (CNS) metastasis that progresses within ≤ four weeks of CNS directed treatment as ascertained by clinical examination(s) and MRI or CT during the main eligibility screening period
PRIMARY TREATMENT: One or more new, active brain/CNS metastasis or the presence of known leptomeningeal disease (LMD) that requires immediate treatment. If treatment within the first cycle of therapy is unlikely to be required, enrollment may be considered, as per the investigator
PRIMARY TREATMENT: Concurrent forms of anti-cancer therapy that have the potential to interfere with efficacy and safety assessments or that may pose increased risk to the participant while on a SMMART-ACT treatment, and as per the investigator (Select hormone therapies are allowed)
PRIMARY TREATMENT: More than one intervening line of therapy for treatment of their cancer since the time of the pre-screening biopsy, exclusive of most maintenance hormone therapies

Note: Participants who have a pre-screening biopsy while receiving a standard of care (SOC) treatment will not be eligible if they receive any additional lines of treatment prior to the start of SMMART-ACT treatment. This treatment will count as one line of intervening therapy
PRIMARY TREATMENT: Untreated and/or uncured hepatitis C virus (HCV) infection, as evidenced by detectable hepatitis B core (HBC) ribonucleic acid (RNA) by polymerase chain reaction (PCR). Prior treatment, concurrent treatment, and natural resolution of HCV infection are not exclusionary given (1) no risk for hepatic decompensation and (2) the intended SMMART-ACT treatment is not expected to exacerbate HCV infection
PRIMARY TREATMENT: Uncontrolled intercurrent illness and infection that may interfere with planned treatment, including, but not limited to, the following:

Symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV),
Unstable angina pectoris or coronary angioplasty, or stenting within < six months prior to enrollment,
Cardiac arrhythmia (ongoing cardiac dysrhythmias of grade ≥ 2 [National Cancer Institute (NCI) CTCAE v 5.0]),
Conditions that require intra-cardiac defibrillators,
Known cardiac metastases,
History of abnormal cardiac valve morphology (≥ grade 2),
Chronic graft versus host disease (GVHD) or immunosuppressive therapy for the control of GVHD
PRIMARY TREATMENT: Severe infection within < four weeks prior to initiation of study therapy, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
PRIMARY TREATMENT: Inability or unwillingness to take oral medication (only for assigned oral study interventions)
PRIMARY TREATMENT: History of allergy to an assigned study agent or its excipients
PRIMARY TREATMENT: Current pregnancy, current breastfeeding, or unwillingness to not breastfeed while receiving study drug(s) or for the minimum required time after the last dose of study drug(s) as specified by the SMMART-ACT drug agents
PRIMARY TREATMENT: Any condition that, in the opinion of the investigator, could jeopardize the participant's safety or adherence to the study protocol
CANCER-SPECIFIC CRITERIA (PROSTATE CANCER): If the screening bone scan shows a "superscan" participants will be excluded from participation. This is defined as an intense symmetric activity in the bones and diminished renal parenchymal activity, such that the presence of additional metastases in the future could not be evaluated

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Oregon Health and Science University
Eli Lilly and Company
AstraZeneca

Investigators

PRINCIPAL_INVESTIGATOR: Lara E Davis, OHSU Knight Cancer Institute

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