A Global, Multicenter, Randomized, Placebo-Controlled Phase 3 Trial to Compare the Efficacy and Safety of Fruquintinib Plus Best Supportive Care to Placebo Plus Best Supportive Care in Patients with Refractory Metastatic Colon Cancer (FRESCO-2)
To evaluate the overall survival of fruquintinib plus BSC compared to placebo plus BSC in subjects with refractory mCRC.
- Provide written informed consent;
- Age >=18 years;
- Histologically and/or cytologically documented metastatic colorectal adenocarcinoma. RAS, BRAF, and microsatellite instability microsatellite instability (MSI)/mismatch repair (MMR) status for each patient must be documented, according to country level guidelines;
- Subjects must have progressed on or been intolerant to treatment with either trifluridine/tipiracil (TAS-102) or regorafenib. Subjects are considered intolerant to TAS-102 or regorafenib if they have received at least 1 dose of either agents and were discontinued from therapy for reasons other than disease progression. Subjects who have been treated with both TAS-102 and regorafenib are permitted. Subjects must also have been previously treated with standard approved therapies: fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and, if RAS wild-type, an anti-EGFR therapy;
- Subjects with microsatellite-high (MSI-H) or mismatch repair deficient (dMMR) tumors must have been treated with immune checkpoint inhibitors if approved and available in the subject's country unless the patient is ineligible for treatment with a checkpoint inhibitor;
- Subjects who received oxaliplatin in the adjuvant setting and developed metastatic disease during or within 6 months of completing adjuvant therapy are considered eligible without receiving oxaliplatin in the metastatic setting. Subjects who developed metastatic disease more than 6 months after completion of oxaliplatin-containing adjuvant treatment must be treated with oxaliplatin-based therapy in the metastatic setting to be eligible;
- Body weight >=40kg;
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;
- Have measurable disease according to RECIST Version 1.1, assessed locally. Tumors that were treated with radiotherapy are not measurable per RECIST Version 1.1, unless there has been documented progression of those lesions;
- Expected survival >12 weeks.
- For female subjects of childbearing potential and male subjects with partners of childbearing potential, agreement to use a highly effective form(s) of contraception, that results in a low failure rate (<1% per year) when used consistently and correctly, starting during the screening period, continuing throughout the entire study period, and for 90 days after taking the last dose of study drug. Such methods include: oral hormonal contraception (combined estrogen/ progestogen, or progestogen-only) associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal ligation, vasectomized partner, or true sexual abstinence in line with the preferred and usual lifestyle of the subject. Highly effective contraception should always be combined with an additional barrier method (eg, diaphragm, with spermicide). The same criteria are applicable to male subjects involved in this clinical trial if they have a partner of childbirth potential, and male subjects must always use a condom.
- Subjects with BRAF-mutant tumors must have been treated with a BRAF inhibitor if approved and available in the subject's home country unless the patient is ineligible for treatment with a BRAF inhibitor.
Randomized Double-Blind Phase III Trial of Vitamin D3 Supplementation in Patients with Previously Untreated Metastatic Colorectal Cancer (SOLARIS)
To compare the progression-free survival (PFS) of patients receiving high-dose cholecalciferol (vitamin D3) in combination with standard chemotherapy (leucovorin calcium, fluorouracil, and oxaliplatin [FOLFOX] or leucovorin calcium, fluorouracil, and irinotecan hydrochloride [FOLFIRI]) and bevacizumab versus those receiving standard-dose vitamin D3 in combination with standard chemotherapy and bevacizumab.
- To compare the objective response rate (ORR) of patients receiving high-dose vitamin D3 in combination with standard chemotherapy + bevacizumab versus those receiving standard-dose vitamin D3 in combination with standard chemotherapy + bevacizumab.
- To compare the overall survival (OS) of patients receiving high-dose vitamin D3 in combination with standard chemotherapy + bevacizumab versus those receiving standard-dose vitamin D3 in combination with standard chemotherapy + bevacizumab.
- To evaluate and compare the toxicity of adding high-dose vitamin D3 versus standard-dose vitamin D3 to chemotherapy + bevacizumab.
- To assess the influence of diet, body mass index, physical activity, and other lifestyle habits on PFS among patients with locally advanced/metastatic colorectal cancer.
- To evaluate the incidence of vitamin D3 deficiency in participants with previously untreated metastatic colorectal cancer.
- To compare the efficacy of high-dose vitamin D3 versus standard-dose vitamin D3 in subgroups of patients defined by baseline plasma calcifediol (25[OH]D) levels.
- To evaluate the prognostic effect of highest-achieved 25(OH)D levels with PFS.
- Histologically confirmed advanced/metastatic colorectal adenocarcinoma for which metastasectomy is not planned.
- No mismatch repair deficiency (dMMR) or high-frequency microsatellite instability (MSI-H) disease.
- Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.
- No prior systemic treatment for metastatic disease.
- Patients may have received prior neoadjuvant or adjuvant chemotherapy and/or chemoradiation. The last course of adjuvant therapy must have been completed > 12 months prior to colorectal cancer recurrence.
- Patients may have received prior standard rectal cancer chemoradiation so long as prior radiotherapy was to =< 25% of bone marrow. Previous radiation therapy must have been completed >= 4 weeks prior to registration.
- No continuous daily use of vitamin D supplements >= 2,000 IU per day for the 12 months prior to registration. Patients may have had continuous daily use of vitamin D supplements >= 2,000 IU per day if total duration < 12 months in the 12 months prior to registration. Patients may have had continuous daily use of vitamin D supplements < 2,000 IU per day for any duration prior to registration.
- Patients must have completed any major surgery or open biopsy >= 4 weeks prior to registration and must have completed any minor surgery or core biopsy >= 1 week prior to registration. (Note: insertion of a vascular access device is not considered major or minor surgery.) Patients must have recovered from the effects of any surgery (e.g. wound is healed, no active infection, no drains, etc.) prior to registration.
- Not pregnant and not nursing. This study involves an agent that has known genotoxic, mutagenic, and teratogenic effects. Therefore, for women of childbearing potential only, a negative serum or urine pregnancy test done =< 14 days prior to registration is required.
- Eastern Cooperative Oncology Group (ECOG) performance status: 0-1.
- Absolute neutrophil count >= 1,500/mm^3.
- Platelet count >= 100,000/mm^3.
- Hemoglobin >= 9 g/dL.
- Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated (Calc.) creatinine clearance (CrCl) > 30 mL/min.
- Calcium =< 1.0 x ULN.
- Corrected for albumin level if albumin not within institutional limits of normal.
- Total bilirubin =< 1.5 x ULN.
- If Gilbert's disease, use direct bilirubin instead of total bilirubin; direct bilirubin =< 1.5 x ULN if patient to receive FOLFIRI; direct bilirubin =< 3.0 x ULN if patient to receive leucovorin, infusional fluorouracil, and oxaliplatin (modified [m]FOLFOX6).
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN.
- AST/ALT < 5 x ULN if clearly attributable to liver metastases.
- Urine protein to creatinine (UPC) ratio < 1 OR urine protein =< 1.
A randomized phase II study of gemcitabine and nab-pacitaxel compared with 5 fluorouracil and lipsomal irnotecan in older patients with treatment naïve metastatic pancreatic cancer
Primary outcome measurements:
Overall survival (OS) [Time Frame: Up to 2 years post treatment]
Secondary outcome measurements:
Instrumental Activities of Daily Living (IADL) [Time Frame: Up to 2 years post treatment]
- Newly diagnosed untreated metastatic adenocarcinoma of the pancreas. However, previous surgery, adjuvant chemotherapy and/or radiation therapy will be allowed, provided radiation therapy is completed at least 2 weeks prior to registration and adjuvant therapy was administered more than 6 months prior to registration. Patients with the following histology are excluded: acinar cell; adenosquamous carcinoma
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Patient is an English speaker with the ability to understand and complete the informed consent and questionnaires
- Leukocytes >= 3,000/mcL (obtained within 4 weeks of registration)
- Absolute neutrophil count >= 1,500/mcL (obtained within 4 weeks of registration)
- Platelets >= 100,000/mcL (obtained within 4 weeks of registration)
- Total bilirubin =< institutional upper limit of normal (ULN) (obtained within 4 weeks of registration)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained within 4 weeks of registration)
- Creatinine =< institutional ULN unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2 (obtained within 4 weeks of registration)
- Glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2 (obtained within 4 weeks of registration)
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this protocol. HIV positive (+) patients who are on ritonavir or/and cobicistat-based regimen must be switched to alternative anti-retroviral therapy (ART)
- 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
- Male patients must agree not to father children while on study
- Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association functional classification. To be eligible for this protocol, patients should be class 2B or better
- Patients must have measurable disease and scans must be done within 4 weeks of registration
- Patients classified to have mild-moderate abnormalities in any of the domains evaluated in the screening geriatric assessment and are classified as "vulnerable" are eligible. Patients classified without any abnormalities ("fit") or with severe cognitive/functional impairment or high co-morbidity score ("frail") on the screening geriatric assessment are ineligible
- Patients must agree not to take any medications or substances that are strong inhibitors or inducers of CYP3A4. Those who are randomized to liposomal irinotecan treatment arm should avoid drugs that are UGT1A1 inhibitors
A Randomized Phase II Study of Nivolumab After Combined Modality Therapy (CMT) in High Risk Anal Cancer
To evaluate whether therapy with nivolumab following combined modality therapy (CMT) improves disease-free survival (DFS) compared with observation in patients with high risk anal carcinoma.
- 1a. To compare nivolumab following combined modality therapy (CMT) with observation in patients with high risk anal carcinoma with regard to:
- 1b. Objective response rate (complete [CR] and partial [PR]), stable disease and progression.
- 1c. Severe toxicity interval.
- 1d. Colostomy-free survival.
- 1e. Overall survival.
- 1f. Toxicity.
- Patients must have histologically proven stage IIB (T3N0M0 only), IIIA (T2N1M0), IIIB (T4N0M0), or IIIC (T3N1M0, T4N1M0) invasive squamous cell carcinoma of the anus or anorectum, according to the American Joint Committee on Cancer (AJCC) 8th edition; this may include tumors of non-keratinizing histology such as basaloid, transitional cell, or cloacogenic histology; individuals with squamous cell carcinoma of the anal margin are eligible if there is evidence of extension of the primary tumor into the anal canal
- Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- Patients must have hemoglobin levels of > 9 g/dL (within 2 weeks prior to registration)
- Patient must have a platelet count of > 100,000/mm^3 (within 2 weeks prior to registration)
- Patient's absolute neutrophil count (ANC) level must be > 1500/mm^3 (within 2 weeks prior to registration)
- Serum creatinine must be =< 1.5 X upper limit of normal (ULN) (within 2 weeks prior to registration)
- Total bilirubin must be < 2 X ULN (within 2 weeks prior to registration)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X institutional upper limit of normal (within 2 weeks prior to registration)
- Albumin >= 3.0 g/dL (within 2 weeks prior to registration)
- Patients known to be human immunodeficiency virus (HIV)+ are permitted; patients with CD4 > 200 and serum HIV viral load of < 200 copies/mm^3 are eligible, and SEE PROTOCOL FOR ADDITIONAL TESTING REQUIREMENTS FOR HIV+ SUBJECTS.
NOTE: HIV testing is not required for eligibility
- For patients registering prior to start of chemoradiotherapy, baseline scans must have been completed within 4 weeks prior to registration
- Women of child bearing potential and sexually active males must use accepted and effective method(s) of contraception and/or abstain from sexual intercourse while on protocol treatment and for at least 5 months after the last dose of nivolumab (for female patients) and for at least 7 months after the last dose of nivolumab (for male patients)
- Any surgery must have been completed >= 4 weeks prior to starting study treatment
- No uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- No prior treatment with an immune checkpoint inhibitor (anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4 monoclonal antibody)
- No patients with immunodeficiency or receiving systemic steroid therapy equivalent to > 10 mg prednisone per day or any other form of immunosuppressive therapy within 7 days prior to Step 1 registration; topical corticosteroid or occasional inhaled corticosteroids are allowed
- No live vaccines within 30 days prior to registration; examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine; seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines and are not allowed
NOTE: no live vaccines may be administered while participating in the trial
- Previously irradiated patients (Arm S) must have received radiation per National Comprehensive Cancer Network guidelines; radiation therapy delivered on protocol (Arm T) will be reviewed