**SJMH is the only site participating in this study.

Eligibility Criteria:

4.1.1 Patient meets all eligibility criteria for treatment of the tumors with the agents listed in Table 1 and has agreed to provide tissue and blood samples for this study.

• Targeted therapy maybe as a singular/monotherapy or in combination with any FDA-approved chemotherapies.

• Patient’s primary or recurrent disease is targeted-treatment naïve or will be treated with a targeted therapy listed in Table 1 different from any previously-received targeted therapy or combination therapy as standard of care.

4.1.2 ECOG Performance Status (PS) 0 or 1. Patients with a PS of 2 may be enrolled only at the discretion of the treating physician and radiologist.

4.1.3 Age 18 or older.

4.1.4 Have an advanced malignancy being treated with one of the agents listed in Table 1. Advanced cancer is cancer that is unlikely to be cured or controlled with treatment. The cancer may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body. Treatment may be given to help shrink the tumor, slow the growth of cancer cells, or relieve symptoms. Patients may be undergoing first or subsequent lines of therapy. In the case where an agent not listed in Table 1 is newly approved for one of the listed tumors, patients undergoing therapy with it will be able to enroll at discretion of the PI. This is to avoid any lag between FDA approval of a previously investigational agent and protocol modifications/updates.

4.1.5 Have an advanced malignancy that meets one of the following criteria:

• Patients must have tumor amenable to image guided or direct vision biopsy and be willing and able to undergo a tumor biopsy for molecular profiling. The biopsy must not be associated with a significant risk of severe or major complications or death. In particular, endoscopic, open or laparoscopic surgical procedures are not to be performed to provide research specimens. However, research specimens may be provided if the patient needs to undergo such procedures for clinical reasons.

Severe or major complications are considered to be those

o Requiring therapy, minor hospitalization (more than overnight but <48 h)

o Requiring major therapy; unplanned increase in level of care, prolonged hospitalization >48 h

o Resulting in permanent adverse sequelae

o Resulting in death

• Patient will be undergoing a procedure due to medical necessity during which the tissue may be collected. The following tumors may be collected only under the conditions specified and not for the sole purpose of the clinical trial:

o Brain biopsies: ONLY if the patient has medical necessity for craniotomy for clinical care.

o Mediastinal, laparoscopic, gastrointestinal, or bronchial endoscopic biopsies: ONLY to be obtained incidentally to a clinically necessary procedure.

4.2 Exclusion Criteria

4.2.1 Uncontrolled intercurrent illness that in the physician’s assessment would pose undue risk for biopsy.

4.2.2 Patients currently enrolled or planning to be co-enrolled (while participating on the 10231 study) on a therapeutically interventional clinical trial aimed to treat the current malignancy.

4.2.3 If the patient is on chronic anticoagulation treatment, they must be able and willing to have this treatment discontinued for the biopsy. Discontinuation procedures will be those of the treating site.

**SJMH, Livonia, and SJMO will be the only site participating**

Eligibility Criteria:

4.1.1 Patient diagnosed with Stage IV colorectal cancer, Stage III/IV non-small cell or small cell lung cancer, metastatic castration-resistant prostate cancer, Stage IV gastroesophageal cancer, Stage III/IV melanoma, newly diagnosed acute myeloid leukemia or treatment refractory multiple myeloma, is undergoing standard of care therapy per NCCN guidelines (https://www.nccn.org/professionals/physician_gls/default.aspx) and has consented to provide longitudinal biospecimens.

4.1.2 Patients with ECOG Performance Status (PS) 0 or 1 may be enrolled retrospectively (i.e.

at time of progression) if archival material is submitted that contains the cancer type for

which the participant is enrolled and that was collected up to 5 years prior to initiation of

a therapy listed in Table 1, assuming that no intervening molecular targeted or

immunotherapies were administered (Archival Material Collection; Section

7.2.1).Patients with a PS of 2 may be enrolled only at the discretion of the treating

physician and radiologist.

4.1.3 Age 13 or older and any gender may be enrolled.

4.1.4 Patients must have tumor amenable to image guided or direct vision biopsy and be

willing and able to undergo a tumor biopsy for molecular profiling

(https://www.ncbi.nlm.nih.gov/pubmed/?term=30285529). The biopsy must not be associated with a significant risk of severe or major complications or death. In particular, endoscopic, open or laparoscopic surgical procedures are not to be performed to provide research biospecimens. However, research biospecimens may be provided if the patient needs to undergo such procedures for clinical reasons. Severe or major complications are considered to be those:

• Requiring therapy, minor hospitalization (more than overnight but <48 h).
• Requiring major therapy; unplanned increase in level of care, prolonged hospitalization >48 h.
• Resulting in permanent adverse sequelae.
• Resulting in death.

The following tumors may be collected only when patients will be undergoing a procedure due to medical necessity during which the tissue may be collected and not for the sole purpose of the clinical study:

• Brain biopsies: ONLY if the patient has medical necessity for craniotomy for clinical care.
• Mediastinal, laparoscopic, gastrointestinal, or bronchial endoscopic biopsies: ONLY to be obtained incidentally to a clinically necessary procedure.

4.1.5 Study participants with CRC, PCA, GEC and MEL may contribute samples for PDM

development if they meet specific PDMR eligibility criteria (Appendix F).

4.1.6 Study participants with LCA and treated with standard of care EGFR, ALK, PD-1 and

PD-L1 antagonists listed in Table 1 and MML may contribute samples directly to

Moonshot investigators if they meet specific DRSN eligibility criteria (Appendix F).

4.1.7 To ensure that individuals who experience diminished decision making capacity during

the course of their cancer treatment are eligible, consent may be provided by a Legally

Authorized Representative (LAR) in accordance with 45 CFR 46.102(i). This protocol

is minimal risk.

**Credentialing Required Prior to Patient Registration. See Section 5.0 of Protocol**

 **Medi-data/RAVE physician training required prior to patient registration**

**The protocol states that PBMC lab tests are required --- if your site does not have the ability to perform this contact RTOG Biospecimen Resource to receive an exemption**

**Data done in RAVE**

Specimen Collection for Banking and Translational Research (Strongly Recommended)

Note: Plasma and whole blood collection are MANDATORY for all patients participating in QOL, and QOL is MANDATORY for the first 410 patients enrolled to the trial.

• PBMCs for banking: Recommended for all patients that consent to tissue banking. Institutions that are unable to process PBMC isolation must contact the RTOG Biospecimen Resource.
  • Pre-treatment
  • During treatment at 12 and 30 months

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Male
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of adenocarcinoma of the prostate within 180 days prior to registration at high risk for recurrence as determined by one of the following combinations (risk group):

  • Gleason Score (GS) = 9, PSA = 150 ng/mL, any T stage
  • GS = 8, PSA < 20 ng/mL, T stage = T2
  • GS = 8, PSA = 20-150 ng/mL, any T stage
  • GS = 7, PSA = 20-150 ng/mL, any T stage

• Baseline serum PSA value performed with an FDA-approved assay (e.g., Abbott, Hybritech), obtained prior to any luteinizing hormone-releasing hormone (LHRH) agonist or antiandrogen therapy, within 180 days of randomization

  • Study entry PSA obtained during the following time frames:

    • 10-day period following prostate biopsy
    • Following initiation of hormonal therapy

• Clinically negative lymph nodes as established by imaging (abdominal and pelvic CT or abdominal and pelvic MRI), nodal sampling, or dissection within 90 days prior to registration

  • Patients with lymph nodes equivocal or questionable by imaging are eligible if the nodes are < 2.0 cm

• No distant metastases (M0) on bone scan within 90 days prior to registration

  • Equivocal bone scan findings are allowed if plain films are negative for metastasis
  • No definite evidence of metastatic disease

• Any patient undergoing brachytherapy must have transrectal ultrasound confirmation of prostate volume < 60 cc, American Urological Association (AUA) score = 15 within 60 days of registration, and no history of prior transurethral resection of the prostate (TURP)

  • Prior TURP is permitted for patients who receive external-beam radiotherapy (EBRT) only

PATIENT CHARACTERISTICS:

• Height, weight, Zubrod performance status 0-1
• Absolute neutrophil count (ANC) = 1,800 cells/mm^3
• Platelets = 100,000 cells/mm^3
• Hemoglobin = 8.0 g/dL (The use of transfusion or other intervention to achieve Hgb = 8.0 g/dL is acceptable)
• Serum creatinine < 2.0 mg/dL
• Creatinine clearance > 40 mL/minute
• Bilirubin < 1.5 x upper limit of normal (ULN)
• ALT or AST < 2.5 x ULN
• No PSA > 150 ng/mL
• Screening calculated ejection fraction = ULN by multiple-gated acquisition (MUGA) scan or by echocardiogram
• Patients, even if surgically sterilized (i.e., status post vasectomy), must agree to practice effective barrier contraception during the entire study treatment period and for 4 months (120 days) after the last dose of study drug
• No prior invasive malignancy (except non-melanoma skin cancer) unless disease-free or not requiring systemic therapy for a minimum of 3 years
• No known hypersensitivity to TAK-700 or related compounds
• No history of adrenal insufficiency

• No history of myocardial infarction, unstable symptomatic ischemic heart disease, ongoing arrhythmias of grade > 2 (NCI CTCAE, version 4.02) thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other cardiac condition (e.g., pericardial effusion restrictive cardiomyopathy) within 6 months prior to registration

  • Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed
• No New York Heart Association Class III or IV heart failure
• No ECG abnormalities of Q-wave infarction, unless identified 6 or more months prior to screening, or QTc interval > 460 msec
• No prior allergic reaction to the drugs involved in this protocol
• No Cushing syndrome
• No severe chronic renal disease or chronic liver disease
• No uncontrolled hypertension despite appropriate medical therapy within 21 days prior to registration (blood pressure of greater than 150 mm Hg systolic and 90 mm Hg diastolic at 2 separate measurements no more than 60 minutes apart during screening visit)
• No serious infection within 14 days prior to registration
• No uncontrolled nausea, vomiting, or diarrhea (CTCAE grade = 3) despite appropriate medical therapy at the time of registration
• No known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of TAK-700, including difficulty swallowing tablets

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Prior testosterone administration is allowed if last administered at least 90 days prior to registration
• No prior radical prostatectomy, cryosurgery for prostate cancer, or bilateral orchiectomy for any reason

• No prior systemic chemotherapy for prostate cancer

  • Prior chemotherapy for a different cancer is allowed
• No prior radiotherapy, including brachytherapy, to the region of the prostate that would result in overlap of radiation therapy fields
• No previous hormonal therapy, such as LHRH agonists (e.g., goserelin, leuprolide), anti-androgens (e.g., flutamide, bicalutamide), estrogens (e.g., DES), or surgical castration (orchiectomy)
• No chronic treatment with glucocorticoids within one year
• No major surgery within 14 days prior to registration
• No other investigational agent
• No other anticancer therapy
• No concurrent hormonal therapies including estrogens or herbal products
• No concurrent ketoconazole or aminoglutethimide
• No chronic use of systemic corticosteroids, such as oral prednisone

Make sure to review the following with your lab to make sure they can perform this:

1.0) Histologically confirmed invasive squamous cell, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, Stage II-B, III-B, IV-A.
2.0) Patients with negative para-aortic nodes.
3.0) PS 0-3.
4.0) No prior chemo or RT treatment allowed.

Drugs: 5FU, Cisplatin

Participating sites: Ann Arbor Only (for Tarlatamab administration)

      Effective as of 1/10/2024: Satellite Sites (Brighton, Canton, Chelsea) can now be used in addition           to Ann Arbor for SoC chemo administration and any other study procedures. 

• 18 years or older
•  Histologically or cytologically confirmed relapsed/refractory SCLC
• Subject has progressed or recurred following 1 platinum-based regimen:  1. documented first disease progression must be during or following first-line platinum-based systemic chemotherapy for ES or LS disease 2. patients who received treatment for LS disease who recur are eligible 3. patients who received adjuvant EP after resection of their SCLC who recur are eligible 4. in countries where SOC first-line systemic treatment for ES disease includes platinum containing chemotherapy in combination with PD-(L)1 inhibitor, it is required that patients have failed PD-(L)1 inhibitor as part of their first-line systemic treatment or are ineligible to receive PD-(L)1 inhibitor therapy 5. is a candidate for any of the 3 SOC therapies to be evaluated in this study as per investigator discretion 
• Provision of evaluable tumor sample for central testing. Tumor sample must be either archival (FFPE blocks collected within 5 years, or slides sectioned within 30 days prior to receipt at the central lab), or a fresh core needle biopsy. Formalin-fixed, paraffin-embedded FNA/cytology samples are allowed (pleural effusion samples are not permitted).  
• Measurable disease as defined per RECIST 1.1 within the 21-day screening period. 
• ECOG PS of 0 or 1
• Minimum life expectancy of 12 weeks
• Adequate organ function

*Credentials required. Check your site's credentialing status.*

Quality of Life substudy (70702) is closed. (effective 8/30/17)
CURRENT SITES CREDENTIALED:
Oakland, SJMH, Livonia, Saginaw, St. John, Macomb, St. Alphonsus, Genesys, Lehigh, Sparrow

-Histologically or cytologically confirmed small cell lung cancer
-Limited-stage disease
-Disease restricted to one hemithorax with regional lymph node metastases, including ipsilateral hilar, ipsilateral and contralateral mediastinal, and ipsilateral supraclavicular lymph nodes
-Patients with cytologically positive pleural or pericardial fluid are NOT eligible
-Patients with disease involvement of the contralateral hilar or supraclavicular lymph nodes are NOT eligible
-Patients must have measurable disease
-Patients may have received one and only one cycle of chemotherapy prior to enrollment, which must have included carboplatin or cisplatin or etoposide
-No prior radiotherapy 
-Patients with complete surgical resection of disease are NOT eligible
-ECOG PS 0-2

Open to Ann Arbor. Satellite sites to come 

Inclusion Criteria:

• Have histologically or cytologically confirmed advanced or metastatic non-small cell lung cancer (NSCLC) that is not amenable to curative intent therapy
• Epidermal growth factor resistance-mutation (EGFRm) must be an Ex19del or Ex21 L858R substitution, as detected by food and drug administration (FDA)-approved or other validated test in a clinical laboratory improvement amendments (CLIA)-certified laboratory in accordance with site standard of care
• Have at least 1 measurable lesion, according to RECIST version (v)1.1, that has not been previously irradiated
• Any toxicities from prior systemic anticancer therapy must have resolved to national cancer institute common terminology criteria for adverse events (NCI-CTCAE) version 5.0 grade 1 or baseline level (except for alopecia [any grade], grade <=2 peripheral neuropathy, or grade <=2 hypothyroidism stable on hormone replacement)
• Have an eastern cooperative oncology group (ECOG) performance status of 0 to 1

Exclusion Criteria:

• Medical history of active interstitial lung disease (ILD), including drug-induced ILD or radiation pneumonitis
• Had major surgery excluding placement of vascular access or tumor biopsy or had significant traumatic injury within 4 weeks before the first dose of anticancer treatments or will not have fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study
• Participant has uncontrolled tumor-related pain (symptomatic lesions amenable to palliative radiotherapy should be treated prior to first dosing)
• Received an investigational treatment that has not been cleared (based on at least 5 half lives of any pharmaceutical treatment) or within 12 months before the planned first dose of study treatment or is currently enrolled in an investigational study
• Has a prior or concurrent second malignancy (other than the disease under study) which natural history or treatment could likely interfere with any study endpoints of safety or the efficacy of the study treatment(s)

1.0) Histo confirmed advanced, persistent or recurrent leiomyosarcinomas of uterus, with documented progression after approp. local Rx.
2.0) Must have measurable dz consisting of abdom, pelvic, chest or other masses defined in 2 dimensions by palpation, xray, CT or US.
3.0) Must have failed local Rx measures and considered incurable.
4.0) PS 0-2

Drugs: Topotecan (provided)