Clinical Trials /

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

NCT03435250

Description:

This study will evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of AG-270 in participants with advanced solid tumors or lymphoma with homozygous MTAP deletion.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Gastric Adenocarcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Lymphoma
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
  • Pancreatic Ductal Adenocarcinoma
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of AG-270 in Participants With Advanced Solid Tumors or Lymphoma With MTAP Loss
  • Official Title: A Phase 1 Study of AG-270 in the Treatment of Subjects With Advanced Solid Tumors or Lymphoma With Homozygous Deletion of MTAP

Clinical Trial IDs

  • ORG STUDY ID: AG270-C-001
  • NCT ID: NCT03435250

Conditions

  • Advanced Solid Tumors
  • Lymphoma

Interventions

DrugSynonymsArms
AG-270MAT2A inhibitorAG-270
AG-270MAT2A inhibitorAG-270/docetaxel
AG-270MAT2A inhibitorAG-270/nab-paclitaxel/gemcitabine
docetaxelTaxotere®AG-270/docetaxel
nab-paclitaxelAbraxane®AG-270/nab-paclitaxel/gemcitabine
gemcitabineGemzar®AG-270/nab-paclitaxel/gemcitabine

Purpose

This study will evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of AG-270 in participants with advanced solid tumors or lymphoma with homozygous MTAP deletion.

Detailed Description

      The purpose of this Phase 1, multicenter, open-label study is to determine the maximum
      tolerated dose (MTD) of AG-270, administered as a single agent or in combination with
      taxane-based chemotherapy, and to characterize its dose-limiting toxicities (DLTs) when given
      daily by mouth to participants with advanced solid tumors or lymphoma with homozygous
      deletion of methylthioadenosine phosphorylase (MTAP).

      In each arm of the study, successive cohorts of participants will receive increasing oral
      doses of AG-270 to determine the MTD, the dose with maximum pharmacologic activity or the
      maximum feasible dose, as a single agent and in combination with taxane-based chemotherapy.
      In the subsequent dose-expansion parts of the study, additional participants in each
      treatment arm will be treated at the MTD (or one of the described alternative doses) to
      further characterize that dose's safety, tolerability, pharmacokinetics (PK) and
      pharmacodynamics (PD), and to detect preliminary evidence of anti-tumor activity.
    

Trial Arms

NameTypeDescriptionInterventions
AG-270ExperimentalAG-270 will be administered on Days 1 to 28 of each 28-day cycle. Treatment will continue until disease progression or unacceptable toxicity.
  • AG-270
AG-270/docetaxelExperimentalAG-270 will be administered daily, starting 1 week prior to docetaxel infusion. Starting on Cycle 1 Day 1, docetaxel (by intravenous infusion [IV]) will be administered once during each 21-day cycle. Treatment with AG-270 and docetaxel will continue until disease progression or unacceptable toxicity.
  • AG-270
  • docetaxel
AG-270/nab-paclitaxel/gemcitabineExperimentalAG-270 will be administered daily, starting 1 week prior to nab-paclitaxel and gemcitabine infusion. Starting on Cycle 1 Day 1, nab-paclitaxel and gemcitabine IV will be administered on Days 1,8, and 15 during each 28-day cycle. Treatment with AG-270, nab-paclitaxel, and gemcitabine will continue until disease progression or unacceptable toxicity.
  • AG-270
  • nab-paclitaxel
  • gemcitabine

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants with DLTs Associated with AG-270 Administration During the First Cycle (First 28 Days) of Treatment
Time Frame:Up to 28 days, on average
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Percentage of Participants with Treatment-related Adverse Events and Serious Adverse Events
Time Frame:Up to 30 weeks, on average
Safety Issue:
Description:
Measure:Changes in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Score
Time Frame:Up to 30 weeks, on average
Safety Issue:
Description:
Measure:Area under the Concentration-versus-time Curve (AUC) from 0 to Time of Last Measurable Concentration (AUC0-t) of AG-270
Time Frame:At multiple time points up to 30 weeks, on average
Safety Issue:
Description:
Measure:AUC from 0 to Infinity (AUC0-∞) of AG-270
Time Frame:At multiple time points up to 30 weeks, on average
Safety Issue:
Description:
Measure:AUC over One Dosing Interval at Steady State (AUCtau,ss) of AG-270
Time Frame:At multiple time points up to 30 weeks, on average
Safety Issue:
Description:
Measure:Time to Maximum Concentration (Tmax) of AG-270
Time Frame:At multiple time points up to 30 weeks, on average
Safety Issue:
Description:
Measure:Maximum Concentration (Cmax) of AG-270
Time Frame:At multiple time points up to 30 weeks, on average
Safety Issue:
Description:
Measure:Trough Concentration (Ctrough) of AG-270
Time Frame:At multiple time points up to 30 weeks, on average
Safety Issue:
Description:
Measure:Half-life (t1/2) of AG-270
Time Frame:At multiple time points up to 30 weeks, on average
Safety Issue:
Description:
Measure:Apparent Volume of Distribution (Vd/F) of AG-270
Time Frame:At multiple time points up to 30 weeks, on average
Safety Issue:
Description:
Measure:Apparent Clearance (CL/F) of AG-270
Time Frame:At multiple time points up to 30 weeks, on average
Safety Issue:
Description:
Measure:Change from Baseline in Circulating Concentration of S-adenosylmethionine (SAM)
Time Frame:Up to 30 weeks, on average
Safety Issue:
Description:
Measure:Change from Baseline in Circulating Concentration of Methionine
Time Frame:Up to 30 weeks, on average
Safety Issue:
Description:
Measure:Clinical Activity of AG-270 in Solid Tumors as Assessed by RECIST V1.1
Time Frame:Up to 30 weeks, on average
Safety Issue:
Description:
Measure:Clinical Activity of AG-270 in Lymphoma as Assessed by Lugano Criteria
Time Frame:Up to 30 weeks, on average
Safety Issue:
Description:
Measure:Duration of Response (DOR)
Time Frame:Up to 30 weeks, on average
Safety Issue:
Description:
Measure:Progression-free Survival (PFS)
Time Frame:Up to 30 weeks, on average
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Agios Pharmaceuticals, Inc.

Trial Keywords

  • MTAP
  • MTAP deletion
  • CDKN2A deletion
  • MAT2A inhibitor
  • Advanced solid tumors
  • Lymphoma

Last Updated

December 8, 2020