Local Consolidative Therapy to Extend the Efficacy of Systemic Therapy in Oligoprogressive Metastatic Cancer, EXTEND-OP Trial

Inclusion Criteria

• Age ≥ 18
• Histologically or cytologically confirmed stage IV cancer
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Candidate for LCT (radiation therapy +/- other local therapies such as surgery, ablation, or embolization) to all sites of progressive disease * Progressive disease will be defined as a discrete radiologic lesion that has not received prior local therapy. Progressive disease will be defined as Response Evaluation Criteria in Solid Tumors (RECIST) (version [v]1.1) defined progression from pre-baseline imaging to baseline imaging at time of screening for the trial. Equivocal findings regarding defining progression for nodal disease will be addressed as below; in the event of ambiguity or equivocal findings for defining oligoprogressive sites of disease at baseline, a study co-Investigator will make a final determination of whether a given site represents progressive disease * Progressive disease must represent an active lesion, which may be defined as the primary tumor site, regional nodal disease, and/or distant metastatic sites
• Candidate for radiation therapy to at least one site of disease
• Between one and five progressive lesions, counted as follows: each lesion (not site) will be counted as one, with the exception of metastatic lymph node stations, which will collectively count as one lesion. Regional nodal stations will be counted as a collective single lesion if oligoprogressive. All progressive lesions must be amenable to local therapy * Counting of oligoprogressive nodal disease will be based on nodal chains. A nodal chain will be considered a single metastatic lesion if the presence of that node results in the patient as having M1 disease per the TNM staging system, American Joint Committee on Cancer (AJCC) version 8.0. In addition, one of the following criteria must be met: a) ≥ 1 lymph node (LN) meets radiologic criteria for metastatic disease via RECIST 1.1 (short axis ≥ 15mm), b) pathologic assessment has confirmed the presence of metastatic cancer cells, and/or c) the LN exhibits imaging signal characteristic of a metastatic lesion (e.g. fludeoxyglucose F 18 (FDG) avidity, contrast enhancement, etc...). In the event of ambiguity or equivocal findings, a study co-Investigator will make a final determination of whether criteria are met. The following caveats apply: ** In patients with a LN exhibiting a short axis ≥ 15mm and who have other diagnoses that can produce enlarged LNs (e.g. indolent chronic lymphocytic leukemia [CLL], sarcoidosis, etc...) or a prior history of benign enlarged LNs will not be considered to have metastatic disease per the discretion of the treating physician ** LN chains that occur bilaterally will be considered separate metastatic sites. For example, left axilla LNs will counted separately from right axilla LNs ** The following midline LN chains will be counted as 1 metastatic site: mediastinal, para-aortic, mesenteric ** The following bilateral LN chains will be counted as 1 metastatic site for unilateral involvement, and 2 for bilateral for involvement: preauricular, cervical and occipital, supraclavicular, infraclavicular, pectoral, axillary, hilar, epitrochlear and brachial, iliac, inguinal and femoral, popliteal
• Baseline imaging must include a scan done within 4 weeks prior to randomization, demonstrating oligoprogressive disease by RECIST (v1.1) criteria compared to pre-baseline imaging * Baseline imaging must be done within 4 weeks prior to randomization, and the following imaging is required: PET/CT scan or CT scan of the chest/abdomen/pelvis. MRI may be substituted as indicated (i.e., CT scan of chest plus MRI abdomen/pelvis). Intracranial imaging is recommended for those histologies/disease sites where intracranial restaging is routinely recommended or appropriate as part of staging/restaging standard-of-care * Pre-baseline imaging must be done 6-16 weeks prior to baseline imaging, and it is recommended to have a comparable imaging modality (matched modalities between pre-baseline and baseline imaging). RECIST v1.1 will be utilized to define any progressive sites of disease, and if between 1 and 5 RECIST-defined progressive sites of disease are identified, patient may be eligible. Non-RECIST-eligible lesions may be eligible if radiographic and/or clinical features support this lesion being progressive * Patients referred for the study that require immediate LCT can receive treatment to central nervous system (CNS) lesions or other symptomatic lesions prior to randomization, but these lesions will be counted towards the total number of oligoprogressive lesions
• Has histologic confirmation of having disease in one of the enrolled disease sites
• Females of childbearing potential must not be breast feeding and must have a negative serum or urine pregnancy test and must agree to use adequate contraception from the time of screening until 3 months after discontinuation of the study medication. Acceptable methods of contraception include total and true sexual abstinence, tubal ligation, hormonal contraceptives that are not prone to drug-drug interactions (IUS levonorgestrel intra-uterine system (Mirena), medroxyprogesterone injections [Depo-Provera]), copper-banded intra-uterine devices, and vasectomized partner. All hormonal methods of contraception should be used in combination with the use of a condom by their sexual male partner. Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause). Women will be considered post-menopausal if they have been amenorrheic for the past 12 months without an alternative medical cause. The following age-specific requirements must also apply: Women < 50 years old: they would be considered post-menopausal if they have been amenorrheic for the past 12 months or more following cessation of exogenous hormonal treatments. The levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) must also be in the post-menopausal range (as per the institution). Women ≥ 50 years old: they would be consider post-menopausal if they have been amenorrheic for the past 12 months or more following cessation of all exogenous hormonal treatments, or have had radiation-induced oophorectomy with the last menses > 1 year ago, or have had chemotherapy-induced menopause with > 1 year interval since last menses, or have had surgical sterilization by either bilateral oophorectomy or hysterectomy
• Non-sterilized males who are sexually active with a female partner of childbearing potential must use adequate contraception for the duration of the study and 3 month after the last dose of study medication. Adequate contraception methods include: birth control pills (eg combined oral contraceptive pill), barrier protection (eg condom plus spermicide, cervical/vault cap or intrauterine device), and abstinence. Patients should not father a child for 6 months after completion of the study medication. Patients should refrain from donating sperm from the start of dosing until 6 months after discontinuing the study medication. If male patients wish to father children they should be advised to arrange for freezing of sperm samples prior to the start of the study medication
• Absolute neutrophil count (ANC) ≥ 500 /mcL (within 4 weeks prior to study enrollment)
• Hemoglobin ≥ 7 g/dL (within 4 weeks prior to study enrollment)
• Platelets ≥ 25,000/mcL (within 4 weeks prior to study enrollment)
• Serum total bilirubin ≤ 1.5 mg//dl (except for subjects with Gilbert syndrome, who may have total bilirubin < 3.0 mg/dl) or direct bilirubin ≤ upper limit of normal (ULN) for subjects with total bilirubin levels > 1.5 mg/dl (within 4 weeks prior to study enrollment)
• Aspartate aminotransferase (serum glutamic oxaloacetic transaminase [SGOT]) ≤ 3 X ULN OR ≤ 5 X ULN for subjects with liver metastases (within 4 weeks prior to study enrollment)
• Alanine aminotransferase (serum glutamic pyruvic transaminase [SGPT]) (within 4 weeks prior to study enrollment)

Exclusion Criteria

• Metastatic effusion (e.g. pleural effusion or ascites). Note that patients with an effusion that is too small to sample will be eligible for the trial
• Leptomeningeal disease if considered active or progressive; while generally patients with leptomeningeal disease will be excluded from the trial, select patients with leptomeningeal disease may be allowed pending approval by the principal investigator or co-principal investigator in situations where patients have controlled or treated leptomeningeal disease
• Peritoneal carcinomatosis
• Cognitively impaired subjects (e.g. inability to sign informed consent.)
• Any condition that, in the opinion of the investigator, would interfere with the study treatment or interpretation of the study results
• Diffuse bone marrow involvement as defined by disease involvement of a bone marrow (BM) biopsy from a site that does not have radiologic evidence of a bone metastasis
• More than 5 prior lines of systemic therapy to treat metastatic disease
• Diagnosis of active scleroderma, lupus, or other rheumatologic disease which in the opinion of the treating radiation oncologist precludes safe delivery of radiotherapy
• Known psychiatric or substance abuse disorder/s that would interfere with trial participation
• Concurrent (synchronous or metachronous) other primary malignancy that in the opinion of the treating physician team presents a substantial risk to the patient’s life as a competing risk of death (against the primary oligoprogressive malignancy being considered for LCT as part of this trial)