Patients with active bleeding are not eligible; specifically, no clinically significant gastrointestinal (GI) bleeding, GI perforation, intra-abdominal abscess or fistula for  months prior to enrollment, no hemoptysis or other signs of pulmonary hemorrhage for  months prior to enrollment; patients with evidence of an acute intracranial or intratumoral hemorrhage on CT or MRI are not eligible (patients with evidence of resolving hemorrhage will be eligible); in patients with CNS tumors, an MRI with ECHO gradient sequences would be required to exclude presence of petechial hemorrhages
Patients with known involvement of the CNS by malignancy will be included if there is no evidence of active bleeding or intratumoral hemorrhage on radiographic imaging
Acute symptomatic CNS hemorrhage
Patients whose screening MRI scan demonstrates intratumoral hemorrhage or peritumoral hemorrhage are not eligible for treatment if deemed significant by the treating physician
Grade  or higher CNS hemorrhage on baseline brain MRI, or history of grade  or higher CNS hemorrhage within  months
Bleeding or thrombotic disorders or participants at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (eg, carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
Bleeding and thrombosis:\r\n* Patients with evidence of active bleeding: intratumoral hemorrhage by current imaging, or bleeding diathesis are not eligible\r\n* Patients with known or prior history in prior  months of esophageal varices are not eligible\r\n* Patients with a history of CNS arterial/venous thromboembolic events including transient ischemic attack (TIA) or cerebrovascular accident (CVA) within  months prior to study enrollment are not eligible\r\n* Patients with a history of deep vein thrombosis (including pulmonary embolism) within  months prior to study enrollment are not eligible\r\n* Patients with a history of hemoptysis or other signs of pulmonary hemorrhage within  months prior to study enrollment are not eligible\r\n* Patients with a history of >= grade  bleeding disorders, vasculitis, or had a significant (>= grade ) episode from the gastrointestinal bleeding, within  months prior to enrollment are not eligible\r\n* For part B: patients with CNS tumors and evidence of new CNS hemorrhage of more than punctate size and/or more than three foci of punctate hemorrhage on baseline magnetic resonance imaging (MRI) obtained within  days prior to study enrollment are not eligible; Note: echocardiogram (ECHO) gradient MRI sequences per institutional guidelines are required for patients with CNS tumors
Subject in whom any major intraoperative bleeding incidences during the surgical procedure occurred (i.e., subject with assignment of an American College of Surgeons Advanced Trauma Life Support Hemorrhage Class of II, III, or IV Hemorrhage);
Recent (within  weeks) history of central nervous system (CNS) hemorrhage unless the hemorrhage is located within the tumor that will be removed en total during surgical debulking or ablated during MLA
Patients with evidence of intra-tumoral hemorrhage >  mm maximal diameter. These subjects should be discussed with the study chair.
Grade >=  hemorrhage within  weeks of patient randomization
Evidence of > grade  central nervous system (CNS) hemorrhage on the baseline MRI scan.
Intracranial hemorrhage grade >  not attributable to recent neurosurgery
Patients with known bleeding disorders or more than punctate intratumoral hemorrhage are excluded
Patients with recent cerebral hemorrhage
Grade  or  hemorrhage within the past  weeks
Patients with evidence of intra-tumoral hemorrhage >  maximal diameter; these subjects should be discussed with the study chair
Evidence of acute intracranial or intratumoral hemorrhage either by magnetic resonance imaging (MRI) or computed tomography (CT) scan; subjects with resolving hemorrhage changes, punctuate hemorrhage, or hemosiderin are eligible
Has a history of spontaneous or tumor-related cerebral hemorrhage; or has cerebral hemorrhage as determined by the screening fludeoxyglucose F- (FDG)-PET-computed tomography (CT) and MRI; this does not include stable post-operative blood products seen on a gradient echo MRI sequence
Subjects who had a prior intracranial hemorrhage, known arteriovenous malformation or aneurysm, head trauma, or evidence of active bleeding;
Patients with evidence of an acute intracranial or intratumoral hemorrhage on computed tomography (CT) or magnetic resonance imaging (MRI) are not eligible (patients with evidence of resolving hemorrhage will be eligible)
Evidence of acute intracranial / intra-tumoral hemorrhage, except for participants with stable grade  hemorrhage.
Intracranial hemorrhage except for tumor associated micro hemorrhage.
Evidence of > grade  CNS hemorrhage on baseline MRI on CT scan
Evidence of > grade  central nervous system (CNS) hemorrhage or > grade  venous thromboembolism
History or presence of digestive tract diseases, including active gastric/duodenal ulcer or ulcerative colitis, or active hemorrhage of an unresected gastrointestinal tumor, or an evaluation by investigators of having any other condition that could possibly result in gastrointestinal tract hemorrhage or perforation;
History of intracranial hemorrhage (either by clinical history or neuroimaging)
Patients with treated supratentorial metastases are allowed if stable, the patient is off steroids and no evidence of intracranial hemorrhage
Patients with evidence of recent intratumoral hemorrhage (within  months of study enrollment), gastrointestinal bleeding, history of coronary artery disease or on anticoagulation therapy
The subject has evidence of acute intracranial or intratumoral hemorrhage either by magnetic resonance imaging (MRI) or computerized tomography (CT) scan; subjects with resolving hemorrhage changes, punctate hemorrhage, or hemosiderin are eligible
Evidence of recent hemorrhage on screening MRI of the brain with the following exceptions: presence of hemosiderin; resolving hemorrhagic changes related to surgery; presence of punctate hemorrhage in the tumor
GI hemorrhage or obstruction experienced within the previous  weeks
Patients who are concurrently receiving or requiring any of the following agents, which may increase the risk for mithramycin related toxicities, such as hemorrhage:\r\n* Thrombolytic agents\r\n* Aspirin or salicylate-containing products, which may increase risk of hemorrhage\r\n* Dextran\r\n* Dipyridamole\r\n* Sulfinpyrazone\r\n* Valproic acid\r\n* Clopidogrel
Evidence of recent (less than  weeks) intracranial hemorrhage.
Presence of diffuse lepto or pachy meningeal carcinomatosis (focal/localized involvement from limited meningeal based metastases acceptable), greater than  cm mid-line shift, uncal herniation, or severe hemorrhage/hydrocephalous (small intra-lesional hemorrhage or anticipated surgical cavity is acceptable); patients with seizure at presentation who have been started on levetiracetam and have been stable for  hours prior to study registration are eligible at the discretion of treating physician
History of intratumoral or peritumoral hemorrhage if deemed significant by the treating physician
Have evidence of significant (ie, symptomatic) intracranial hemorrhage.
Evidence of a new intracranial or intratumoral hemorrhage that is larger than a punctuate size on baseline magnetic resonance imaging (MRI) obtained within  days prior to study registration
Has an ongoing or previous history of spontaneous intratumoral hemorrhage.
Presence of clinically significant increased intracranial pressure (e.g. impending herniation) or hemorrhage, uncontrolled seizures, or requirement for immediate palliative treatment.
Patients who are concurrently receiving or requiring any of the following agents, which may increase the risk for mithramycin related toxicities, such as hemorrhage:\r\n* Thrombolytic agents\r\n* Aspirin or salicylate-containing products, which may increase risk of hemorrhage\r\n* Dextran\r\n* Dipyridamole\r\n* Sulfinpyrazone\r\n* Valproic acid\r\n* Clopidogrel
Subjects with a history of significant hemoptysis per the treating physician's judgment, cerebral hemorrhage or clinically significant gastrointestinal (GI) hemorrhage or myocardial infarction (MI) within the past  months
Evidence of any significant intracranial hemorrhage, as determined by the treating investigator, within  weeks from registration or as seen on most recent MRI prior to screening/baseline MRI
Patients must not have evidence of new CNS hemorrhage on baseline MRI obtained within  days prior to study enrollment
Glioma patients with evidence of intracranial or intratumoral hemorrhage either by MRI or CT scan
Presence of diffuse leptomeningeal carcinomatosis (focal/localized involvement is acceptable), >  cm mid-line shift, uncal herniation or significant hemorrhage/hydrocephalous (small intra-lesional hemorrhage is acceptable); patients with seizure at presentation who have been started on levetiracetam and have been stable for  hours prior to study registration are eligible at the discretion of treating physician
Evidence of recent hemorrhage on baseline MRI of the brain. However, patients with clinically asymptomatic presence of hemosiderin, resolving hemorrhagic changes related to surgery, or presence of punctuate hemorrhage in the tumor are eligible.
Any significant bleeding (greater than or equal to grade , hemorrhage) that is not related to the primary colon tumor within  months before randomization.
Evidence of CNS hemorrhage on baseline MRI or CT scan (except for post-surgical, asymptomatic Grade  hemorrhage that has been stable for at least  months for subjects enrolled prior to Amendment  and for at least  weeks in subjects enrolled after Amendment  is approved).
Presence of clinically significant increased intracranial pressure (e.g. impending herniation) or hemorrhage, uncontrolled seizures, or requirement for immediate palliative treatment
History of intratumoral or peritumoral hemorrhage if deemed significant by the treating physician
Magnetic resonance imaging (MRI) echocardiogram (ECHO) gradient sequences are required to evaluate for the presence or absence of central nervous system (CNS) hemorrhage; patients with intra-tumoral and/or CNS hemorrhage are not eligible for study entry except:\r\n* Patients with asymptomatic intra-tumoral hemorrhage of punctate size, at the time of diagnosis, after surgery, and/or any time during protocol therapy\r\n* Patients with asymptomatic post-operative hemorrhage in and/or around the surgical cavity are eligible for study entry; additional imaging studies are not required, but in the event a repeat MRI is performed for clinical reasons the post-operative hemorrhage must not have progressed
Evidence of recent hemorrhage on baseline MRI of the brain with the following exceptions:
Presence of punctate hemorrhage in the tumor.
At an increased risk of hemorrhage
The subject has evidence of acute intracranial or intratumoral hemorrhage either by magnetic resonance imaging (MRI) or computed tomography (CT) scan; subjects with resolving hemorrhage, punctate hemorrhage, or hemosiderin are eligible
Patients with known bleeding disorders or more than punctate intratumoral hemorrhage are excluded
Evidence of new intracranial hemorrhage of more than punctate size on MRI assessment obtained within  days prior to study enrollment for Participants with HGG
History of Grade  (CTCAE v) or greater acute intracranial hemorrhage.
Active gastrointestinal (GI) or intracranial hemorrhage
Patients whose MRI scan demonstrates intratumoral hemorrhage or peritumoral hemorrhage are not eligible for treatment if deemed significant by the treating physician
Evidence of frank hemorrhage or impending herniation on baseline brain imaging; NOTE: asymptomatic micro-hemorrhage is allowed
Patients under treatment with anticoagulants or with coagulation disorders or with signs of hemorrhage at baseline
Patients with evidence of spontaneous hemorrhage greater than . cm unrelated to surgery
Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy
Patients under treatment with anticoagulants or with coagulation disorders or with signs of hemorrhage at baseline
Evidence of recent hemorrhage on post-operative contrast enhanced brain MRI (except hemosiderin, resolving hemorrhage changes related to surgery, presence of punctuate hemorrhage in tumor).
Patients with recent history of hemorrhage and patients predisposed to hemorrhage due to coagulopathies or structural anomalies.
Subjects with severe hemorrhage, or history of severe hemorrhage
No evidence of hemorrhage on the baseline MRI or CT scan other than those that are Grade ?  and either post-operative or stable on at least two consecutive scans.
Pulmonary hemorrhage of Grade ? within  days prior to first dose of study treatment
Evidence of CNS hemorrhage CTCAE ? grade  on baseline MRI.
Patient is at increased bleeding risk due to concurrent conditions (eg, major injuries or surgery within the past  days prior to start of study treatment, history of CVA, transient ischemic attack, subarachnoid hemorrhage, or clinically significant hemorrhage within the past  months).
Evidence of recent hemorrhage on baseline MRI of the brain.
Evidence of central nervous system (CNS) hemorrhage on baseline MRI or computed tomography (CT) scan (except for grade  hemorrhage that has been stable for at least  months)
Subject has uncontrolled hemorrhage
In patients with CNS tumors or known CNS metastases, evidence of intracranial or intratumoral hemorrhage of more than punctuate size and/or more than  foci of punctuate hemorrhage on baseline magnetic resonance imaging (MRI) obtained within  days prior to study registration
Newly developed inoperable brain metastases (first occurrence) without associated hemorrhage or midline shift
No evidence of recent hemorrhage at pre-registration MRI of the brain, however the following are permitted: presence of hemosiderin, resolving hemorrhagic changes related to surgery, and presence of punctate hemorrhage in the tumor
Evidence of significant intracranial hemorrhage
Patients at risk of non-disease related major bleeding (eg, recent GI hemorrhage or neurosurgery, within previous  days).
Evidence of recent (less than  weeks) hemorrhage on postoperative MRI of the brain; however, patients with clinically asymptomatic presence of hemosiderin, resolving hemorrhagic changes related to surgery, and presence of punctate hemorrhage in the tumour are permitted entry into the study
History of CNS hemorrhage within  days of study entry. This criterion may be waived at the investigator's request if the CNS hemorrhage was asymptomatic, with approval of the Medical Monitor
Diagnosis of intracranial hemorrhage within the past  months, including intratumoral hemorrhage into brain metastases from a systemic cancer
History of significant hemorrhage (requiring hospitalization or transfusion) outside of a surgical setting within the last  months
Any history of significant hemorrhage (requiring hospitalization or transfusion) within the last  months (excluding hemorrhage during operative procedure)
Patients must not have evidence of significant intracranial hemorrhage
Evidence for hemorrhage within any of the brain metastases.
Patient must not have evidence of a new CNS hemorrhage greater than . cm on baseline MRI obtained =<  days prior to study enrollment
Patients with recent cerebral hemorrhage
Patients with recent cerebral hemorrhage
No hemorrhage after treatment.