Study of AG-270 in Participants With Advanced Solid Tumors or Lymphoma With MTAP Loss

Inclusion Criteria

• Inclusion Criteria: AG-270 Monotherapy 1. Be ≥18 years of age; 2. Have a histologically confirmed diagnosis of an advanced solid tumor or lymphoma that has progressed in spite of at least one prior line of treatment, and for which additional effective standard therapy is not available. For this study, effective standard therapy is defined as treatment that has been shown to be curative and/or to prolong survival. In addition, participants who are considered to not be candidates for standard therapy or who decline standard therapy are eligible for this study; in such cases, documentation of the reason for omitting or declining a standard therapy is required; 3. Have evidence of homozygous loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) and/or MTAP in the participant's tumor tissue; 4. Have disease that can be clinically evaluated for improvement or progression. In the dose-expansion phase of the study arm, participants must have disease that is measurable, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria for solid tumors (Eisenhauer et al, 2009) or the Lugano criteria for lymphoma (Cheson et al, 2014); 5. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2; 6. Have a hemoglobin ≥9.0 grams per deciliter (g/dL) without red blood cell transfusion for ≥1 month; 7. Have an absolute neutrophil count (ANC) ≥1.0 × 10^9/liter (L); 8. Have a platelet count ≥75 × 10^9/L; 9. Have a serum total bilirubin ≤1.5 × upper limit of normal (ULN); 10. Have an alanine aminotransferase (ALT) ≤3.0 × ULN. (Note: There are no specific requirements for aspartate aminotransferase (AST) or Alkaline phosphatase [ALP]); 11. Have a serum creatinine ≤1.5 × ULN; 12. Be fully recovered from major surgery and from the acute toxic effects of prior chemotherapy and radiotherapy. Residual chronic toxicities of prior therapy ≤Grade 2 (eg, peripheral neuropathy, residual alopecia) are allowed; 13. Female participants who are pre-menopausal or have experienced menopause for less than 2 years and who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion must have a negative serum pregnancy test during screening and a serum or urine pregnancy test must be re-confirmed as negative no more than 72 hours before starting AG-270. Females of reproductive potential as well as fertile men with partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use 2 effective forms of contraception (including at least 1 barrier form) from the time of giving informed consent, during the study, and for 6 months (for females) and for 3 months (for males) following the last dose of AG-270. Effective forms of contraception are defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier methods (eg, synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization; 14. Able to understand and has provided written informed consent. A legally authorized representative may consent on behalf of a participant who is otherwise unable to provide informed consent, if acceptable to and approved by the site and/or site's Institutional Review Board (IRB)/Independent Ethics Committee (IEC). AG-270 in Combination with Docetaxel 1. a. Be ≥18 years of age; 2. a. Have histologically confirmed diagnosis of non-small cell lung cancer (NSCLC) that has been treated with no more than 2 prior lines of cytotoxic chemotherapy in the setting of metastatic (Stage 4) disease. Three prior lines of cytotoxic chemotherapy for metastatic disease are allowed if one of the 3 lines was a maintenance treatment. Participants with solid tumors other than NSCLC for which docetaxel is indicated are eligible for the dose-escalation arm, but they also must have received no more than 2 prior lines of cytotoxic chemotherapy in the setting of metastatic disease; For both participants with NSCLC and participants with other malignancies prior treatment with taxanes is permitted, but prior treatment with docetaxel is not allowed. There is no limitation on the number of non-cytotoxic therapies that a participant with NSCLC or with another malignancy may have received; 3. a. Have evidence of homozygous loss of CDKN2A and/or MTAP in the participant's tumor tissue. In the dose expansion phase of the combination, participants must have homozygous MTAP deletion; 4. a. Have disease that can be clinically evaluated for improvement or progression. In the dose-expansion phase of this study arm, participants must have disease that is measurable, as defined by the RECIST Version 1.1 criteria for solid tumors (Eisenhauer et al, 2009); 5. a. Have an ECOG PS of ≤1; 6. a. Have a hemoglobin ≥9.0 g/dL without red blood cell transfusion for ≥1 month; 7. a. Have an ANC ≥1.5 × 10^9/L; 8. a. Have a platelet count ≥100 × 10^9/L; 9. a. Have a serum total bilirubin ≤1.5 × ULN; 10. a. Have an ALT ≤3.0 × ULN. If ALP is >2.5 × ULN and the increase in ALP cannot be attributed to bone metastases or other bone disease then the participant must have ALT and AST values that are both <1.0 × ULN; this requirement conforms with the current label for Taxotere®; 11. a. Have a serum creatinine ≤1.5 × ULN; 12. a. Meet any criteria necessary for the safe and proper use of docetaxel; 13. a. Be fully recovered from major surgery and from the acute toxic effects of prior chemotherapy and radiotherapy. Residual chronic toxicities of prior therapy ≤ Grade 2 (eg, peripheral neuropathy, residual alopecia) are allowed; 14. a. Female participants who are pre-menopausal or have experienced menopause for less than 2 years and who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion must have a negative serum pregnancy test during Screening and a serum or urine pregnancy test must be re-confirmed as negative no more than 72 hours before starting AG-270. Females of reproductive potential as well as fertile men with partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use 2 effective forms of contraception (including at least 1 barrier form) from the time of giving informed consent, during the study, and for 6 months (for females) and for 3 months (for males) following the last dose of AG-270. Effective forms of contraception are defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier methods (eg, synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization; 15. a. Able to understand and has provided written informed consent. A legally authorized representative may consent on behalf of a participant who is otherwise unable to provide informed consent, if acceptable to and approved by the site and/or site's IRB/IEC. AG-270 in Combination with nab-Paclitaxel and Gemcitabine 1. b. Be ≥18 years of age; 2. b. Have locally advanced or metastatic pancreatic ductal adenocarcinoma characterized by CDKN2A deletion and/or MTAP deletion; 3. b. Have evidence of homozygous loss of CDKN2A and/or MTAP in the participant's tumor tissue. In the dose expansion phase of the combination, participants must have homozygous MTAP deletion; 4. b. Have received no more than 1 previous line of cytotoxic chemotherapy for advanced or metastatic disease. Participants may have been treated with cytotoxic chemotherapy in the adjuvant setting if the final dose of such adjuvant treatment was given at least 6 months before administration of the first doses of AG-270, nab-paclitaxel, and gemcitabine; treatment with cytotoxic chemotherapy in the adjuvant setting will not be counted in the lines of previous cytotoxic chemotherapy for advanced or metastatic disease. There is no limitation on the number of non-cytotoxic therapies that a participant may have received; 5. b. Have an ECOG PS of ≤1; 6. b. Have a hemoglobin ≥9.0 g/dL without red blood cell transfusion for ≥1 month; 7. b. Have an ANC ≥1.5 × 10^9/L; 8. b. Have a platelet count ≥100 × 10^9/L; 9. b. Have a serum total bilirubin ≤1.5 × ULN; 10. b. Have an ALT ≤3.0 × ULN. (Note: There are no specific requirements for AST or ALP.); 11. b. Have a serum creatinine ≤1.5 × ULN; 12. b. Meet any criteria necessary for the safe and proper use of nab-paclitaxel and gemcitabine; 13. b. Be fully recovered from major surgery and from the acute toxic effects of prior chemotherapy and radiotherapy. Residual chronic toxicities of prior therapy ≤ Grade 2 (eg, peripheral neuropathy, residual alopecia) are allowed; 14. b. Female participants who are pre-menopausal or have experienced menopause for less than 2 years and who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion must have a negative serum pregnancy test during Screening and a serum or urine pregnancy test must be re-confirmed as negative no more than 72 hours before starting AG-270. Females of reproductive potential as well as fertile men with partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use 2 effective forms of contraception (including at least 1 barrier form) from the time of giving informed consent, during the study, and for 6 months (for females) and for 3 months (for males) following the last dose of AG-270. Effective forms of contraception are defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier methods (eg, synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization; 15. b. Able to understand and has provided written informed consent. A legally authorized representative may consent on behalf of a participant who is otherwise unable to provide informed consent, if acceptable to and approved by the site and/or site's IRB/IEC. Exclusion Criteria (All Treatment Arms): 1. Have a primary central nervous system (CNS) malignancy (eg, glioblastoma multiforme [GBM]); 2. Have metastasis to the CNS that is symptomatic and/or requires therapy with corticosteroids or anti-convulsant medication. However, participants who have completed treatment (radiation therapy) for CNS metastases and do not require continued treatment with corticosteroids or anti-convulsants may be enrolled in this study; 3. Have a history of Gilbert's syndrome; 4. Have a degenerative retinal disease. Retinal diseases that require a participant's exclusion include: glaucoma (with the exception of narrow angle glaucoma), hereditary retinal diseases such as retinitis pigmentosa; retinal arterial occlusive disease; and retinal disease with advanced scarring, to include age-related macular degeneration and myopic degeneration with geographic atrophy; 5. Have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of AG-270, including any unresolved nausea, vomiting, or diarrhea that is National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >1; 6. Have had significant active cardiac disease within 6 months prior to the start of study treatment, including any of the following: 1. New York Heart Association (NYHA) class III or IV congestive heart failure; 2. Acute myocardial infarction or angina pectoris; 3. Stroke; 4. Uncontrolled cardiac arrhythmia (participants with rate-controlled atrial fibrillation are not excluded). 7. Have a heart-rate corrected QT interval using Fridericia's method (QTcF) >470 milliseconds (msec); 8. Have any other concurrent severe and/or uncontrolled concomitant medical condition that could compromise participation in the study (eg, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection); 9. Have received systemic anti-cancer treatment or radiotherapy less than 2 weeks before the first dose of AG-270. Participants with castration-resistant prostate cancer may continue therapy with a luteinizing hormone releasing hormone (LHRH) agonist while participating in this study. Continuation of supportive therapy with bisphosphonates or denosumab is also allowed, regardless of the underlying malignancy; 10. Have received radioimmunotherapy (eg, 131I-tositumomab, 90Y-ibritumomab tiuxetan) less than 6 weeks before the first dose of AG-270; 11. Have received treatment with a therapeutic antibody less than 4 weeks before the first dose of AG-270. A minimum 2-week period between the last treatment with a therapeutic antibody and the first dose of AG-270 may be permitted in participants with rapidly progressive or aggressive subtypes of lymphoma following discussion with the medical monitor; 12. Have received treatment with an investigational small molecule less than 2 weeks before the first dose of AG-270. In addition, the first dose of AG-270 should not occur before a period greater than or equal to 5 half-lives of the investigational small molecule has elapsed; 13. Require continued treatment with a medication that is known to be a strong inhibitor of cytochrome P450 (CYP)3A enzymes. (Treatment with moderate or weak CYP enzyme inhibitors is allowed.); 14. Require continued treatment with a medication that is known to be a strong inducer of CYP3A; 15. Require continued treatment with a medication that is known to be a strong inhibitor of CYP2C8; 16. Require continued treatment with a medication that is a sensitive CYP2C9 substrate with a narrow therapeutic index; 17. Require continued treatment with medications that are known to carry a risk of torsades de pointes; 18. Are pregnant or breastfeeding; 19. Have any other medical or psychological condition deemed by the Investigator to likely interfere with the participant's ability to give informed consent or participate in the study; 20. Are unable to take no food or liquids other than water for 2 hours before and 2 hours after each dose of AG-270.