Clinical Trials /

Avelumab and M6620 or Nedisertib for the Treatment of DDR Deficient Metastatic or Unresectable Solid Tumors

NCT04266912

Description:

This phase I/II trial studies the side effects and best dose of avelumab with M6620 or nedisertib in treating patients with DNA damage repair (DDR) deficient solid tumors that have spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). DDR deficiency refers to a decrease in the ability of cells to respond to damaged DNA and to repair the damage, which can be caused by genetic mutations. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. M6620 and nedisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving avelumab together with M6620 or nedisertib may help to control DDR deficient metastatic or unresectable solid tumors.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Avelumab and M6620 or Nedisertib for the Treatment of DDR Deficient Metastatic or Unresectable Solid Tumors
  • Official Title: DNA Damage Repair (DDR) Inhibitor-Based Basket of Baskets Trial in Patients With Advanced Solid Tumors Harboring Aberrations In DDR Genes (D-BoB)

Clinical Trial IDs

  • ORG STUDY ID: 2018-1059
  • SECONDARY ID: NCI-2019-07598
  • SECONDARY ID: 2018-1059
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04266912

Conditions

  • Advanced Malignant Solid Neoplasm
  • Metastatic Malignant Solid Neoplasm
  • Unresectable Malignant Solid Neoplasm

Interventions

DrugSynonymsArms
ATR Kinase Inhibitor M6620M 6620, M6620, VX-970Arm A (avelumab, ATR kinase inhibitor M6620)
AvelumabBavencio, MSB-0010718C, MSB0010718CArm A (avelumab, ATR kinase inhibitor M6620)
Nedisertib3-Pyridazinemethanol, alpha-(2-Chloro-4-fluoro-5-(7-(4-morpholinyl)-4-quinazolinyl)phenyl)-6-methoxy-, (alphaS)-, M 3814, M-3814, M3814, MSC 2490484A, MSC-2490484A, MSC2490484AArm B (avelumab, nedisertib)

Purpose

This phase I/II trial studies the side effects and best dose of avelumab with M6620 or nedisertib in treating patients with DNA damage repair (DDR) deficient solid tumors that have spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). DDR deficiency refers to a decrease in the ability of cells to respond to damaged DNA and to repair the damage, which can be caused by genetic mutations. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. M6620 and nedisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving avelumab together with M6620 or nedisertib may help to control DDR deficient metastatic or unresectable solid tumors.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety and tolerability of the combination of ATR kinase inhibitor M6620
      (M6620) and avelumab in patients with deoxyribonucleic acid (DNA) damage response (DDR)
      deficient advanced solid tumors. (Arm A: M6620 + avelumab) II. To establish the maximum
      tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of M6620 and
      avelumab in patients with DDR deficient advanced solid tumors. (Arm A: M6620 + avelumab) III.
      To confirm the safety and tolerability of the combination of nedisertib (M3814) and avelumab
      in patients with DDR deficient advanced solid tumors. (Arm B: M3814 + avelumab)

      SECONDARY OBJECTIVES:

      I. To determine the clinical benefit of the combination as defined by clinical benefit rate
      (CBR) - complete response [CR] + partial response [PR] + stable disease [SD] > 6 months (CR +
      PR + SD > 6 months). (Arm A: M6620 + avelumab) II. To assess clinical benefit of the
      combination as defined by objective response rate (ORR), overall survival (OS), and
      progression free survival (PFS). (Arm A: M6620 + avelumab) III. To determine the clinical
      benefit of the combination of M3814 and avelumab, as defined by CBR (CR + PR + SD > 6
      months). (Arm B: M3814 + avelumab) IV. To assess clinical benefit of the combination as
      defined by ORR, OS and PFS. (Arm B: M3814 + avelumab)

      EXPLORATORY OBJECTIVES:

      I. To evaluate clinical benefit of the combination of M6620 and avelumab based on specific
      DDR aberrations. (Arm A: M6620 + avelumab) II. To evaluate clinical benefit of the
      combination of M6620 and avelumab based on DDR gene expression signatures. (Arm A: M6620 +
      avelumab) III. To evaluate the impact of treatment on programmed death ligand 1 (PD-L1)
      expression and immune cell populations. (Arm A: M6620 + avelumab) IV. To assess potential
      mechanisms of resistance by comparing pre- and on-treatment biopsies in responders and
      non-responders. (Arm A: M6620 + avelumab) V. To evaluate the pharmacokinetic (PK) and
      pharmacodynamic (PD) profile of M6620 in combination with avelumab in patients with DDR
      deficient advanced solid tumors. (Arm A: M6620 + avelumab) VI. To evaluate clinical benefit
      of the combination of M3814 and avelumab based on DDR gene expression signatures. (Arm B:
      M3814 + avelumab) VII. To evaluate the impact of treatment on PD-L1 expression and immune
      cell populations. (Arm B: M3814 + avelumab) VIII. To assess potential mechanisms of
      resistance by comparing pre- and on-treatment biopsies in responders and non-responders. (Arm
      B: M3814 + avelumab) IX. To evaluate the PK and PD profile of M3814 in combination with
      avelumab in patients with DDR deficient advanced solid tumors. (Arm B: M3814 + avelumab)

      OUTLINE: This is a phase I, dose-escalation study of ATR kinase inhibitor M6620, followed by
      a phase II study. Patients are assigned to 1 of 2 arms.

      ARM A: Patients receive avelumab intravenously (IV) over 60 minutes on days 1 and 15 and ATR
      kinase inhibitor M6620 IV over 60 minutes on days 1, 8, 15, and 22. Cycles repeat every 28
      days in the absence of disease progression or unacceptable toxicity.

      ARM B: Patients receive avelumab IV over 60 minutes on days 1 and 15 and nedisertib orally
      (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 60 and 90 days, then every
      12 weeks for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (avelumab, ATR kinase inhibitor M6620)ExperimentalPatients receive avelumab IV over 60 minutes on days 1 and 15 and ATR kinase inhibitor M6620 IV over 60 minutes on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • ATR Kinase Inhibitor M6620
  • Avelumab
Arm B (avelumab, nedisertib)ExperimentalPatients receive avelumab IV over 60 minutes on days 1 and 15 and nedisertib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Avelumab
  • Nedisertib

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects must have histologically confirmed malignancy that is metastatic or
             unresectable and for which standard curative measures do not exist or are no longer
             effective

          -  Subjects will be eligible for this study based on the presence of actionable
             aberrations in one or more of the following DNA damage response (DDR) genes: ARID1A,
             ATM, ATR, ATRX, BAP1, BARD1, BRCA1/2, BRIP1, CDK12, CHEK2, FANCA, FANCC, FANCD2,
             FANCE, FANCF, FANCM, MRE11A, MSH2, NBN (NBS1), PALB2, RAD51, RAD51C, RAD51D, SMARCB1,
             and VHL, or other related genes at the discretion of the principal investigator in
             consultation with the MD Anderson Cancer Center Institute or Personalized Cancer
             Therapy Precision Oncology Decision Support (PODS) group. Variant interpretation for
             actionability will be performed by PODS

          -  The collection of archival tumor tissue (within 1 year prior to study enrollment) will
             be mandatory. Tumor biopsies on cycle 1 day 15 will be mandatory, all other biopsy
             time points are not mandatory but will be strongly encouraged where feasible. These
             include at baseline and at disease progression

          -  Subjects must have received at least 1 line of systemic therapy in the
             advanced/metastatic setting. Subjects with diseases without known effective options,
             and subjects who had declined standard of care therapy prior to study introduction are
             also eligible

          -  Subjects must have measurable disease per Response Evaluation Criteria in Solid Tumors
             (RECIST) version (v) 1.1, or patients may have bone metastatic disease evaluable by
             Prostate Cancer Working Group 3 (PCWG3) for subjects with metastatic
             castration-resistant prostate cancer (CRPC), or according to tumor evaluation criteria
             best suited and accepted for the tumor type to be evaluated

          -  Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          -  Subjects must have a life expectancy >= 12 weeks

          -  Absolute neutrophil count >= 1.5 x 10^9/L

          -  Platelets >= 100 x 10^9/L

          -  Hemoglobin >= 9 g/dL or =< 5.6 mmol/L

          -  Total bilirubin =< 1.5 X the institutional upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/
             alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT) =< 2.5 X
             institutional ULN or =< 5 X institutional ULN in the presence of liver metastases

          -  Serum creatinine =< 2 X ULN or estimated creatinine clearance >= 30 mL/min according
             to the Cockcroft-Gault formula

          -  Female patients of childbearing potential must have a negative serum or urine
             pregnancy test at screening (and again at baseline just prior to first administration
             of study drugs)

          -  Female patients of non-childbearing potential must meet at least 1 of the following
             criteria:

               -  Achieved postmenopausal status, defined as follows: cessation of regular menses
                  for at least 12 consecutive months, with no alternative pathological or
                  physiological cause, and have a serum follicle-stimulating hormone (FSH) level
                  confirming the postmenopausal state

               -  Have undergone a documented hysterectomy and/or bilateral oophorectomy

               -  Have medically confirmed ovarian failure All other female patients (including
                  female patients with tubal ligation) are considered to be of childbearing
                  potential

          -  Women of childbearing potential and fertile men must agree to use adequate
             contraception when sexually active from signing of the informed consent form for the
             full study until at least 6 months after the last study drug administration. Patients
             must agree to utilize 2 reliable and acceptable methods of contraception
             simultaneously. A man is considered fertile after puberty unless permanently sterile
             by bilateral orchiectomy. Men taking part in this study are advised not to father a
             child during and up to 6 months after treatment; prior to treatment, advice should be
             sought for conserving sperm due to the chance of irreversible infertility as a
             consequence of treatment. Female partners of childbearing potential from male study
             patients have to use adequate contraception / birth control between signing of the
             informed consent and 6 months after the last administration of the study drug if the
             male study patient is not sterilized. The investigator or a designated associate is
             requested to advise the patient how to achieve highly effective birth control. Highly
             effective (failure rate of less than 1% per year) contraception methods, when used
             consistently and correctly, include:

               -  Combined (estrogen and progestin containing: oral, intravaginal, transdermal) and
                  progestin-only (oral, injectable, implantable) hormonal contraception associated
                  with inhibition of ovulation

               -  Intra-uterine device or intrauterine hormone-releasing system

               -  Bilateral tubal occlusion or vasectomized partner (provided that partner is the
                  sole sexual partner and has received medical assessment of the surgical success)

               -  Sexual abstinence (reliability to be evaluated in relation to the duration of the
                  clinical trial and the preferred and usual lifestyle of the patient) Male
                  patients with a female partner of reproductive potential must use a condom and
                  ensure that an additional form of contraception is also used during treatment and
                  until 6 months after last study drug administration. Patients must agree to
                  utilize 2 reliable and acceptable methods of contraception simultaneously

          -  Evidence of a personally signed and dated informed consent document indicating that
             the patient has been informed of all pertinent aspects of the study

          -  Willing and able to comply with scheduled visits, treatment plan, laboratory tests,
             and other procedures

        Exclusion Criteria:

          -  Anticancer systemic therapy or radiotherapy within 4 weeks or 5 half-lives, whichever
             is shorter prior to starting the study agents. Prior palliative radiotherapy to
             metastatic lesion(s) is permitted, ,provided it has been completed 2 weeks prior to
             study enrollment, and no clinically significant toxicities are expected (e.g.,
             mucositis, esophagitis)

          -  Known symptomatic brain metastases requiring steroids. Patients with previously
             treated diagnosed brain metastases are eligible if they have completed their treatment
             and have recovered from the acute effects of radiation therapy or surgery prior to
             study enrollment, have discontinued corticosteroid treatment for these metastases for
             at least 4 weeks and are neurologically stable

          -  Current use of immunosuppressive medication at the time of study enrollment, EXCEPT
             for the following permitted steroids:

               -  Intranasal, inhaled, topical steroids, eye drops, or local steroid injection
                  (e.g., intra-articular injection)

               -  Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or
                  equivalent

               -  Steroids as premedication for hypersensitivity reactions (e.g. computed
                  tomography (CT) scan premedication)

          -  Subjects who had major surgery within 4 weeks prior to study enrollment

          -  Known prior severe hypersensitivity to investigational products or any component in
             their formulations, including known severe hypersensitivity reactions to monoclonal
             antibodies (National Cancer Institute [NCI] Common Terminology Criteria for Adverse
             Events [CTCAE] v5 grade >= 3)

          -  Active infection requiring systemic therapy

          -  Known history of immune-mediated colitis, inflammatory bowel disease, pneumonitis, and
             pulmonary fibrosis

          -  Active or prior autoimmune disease that may deteriorate when receiving an
             immunostimulatory agent. Patients with type I diabetes, vitiligo, psoriasis, or hypo-
             or hyperthyroid disease not requiring immunosuppressive treatment are eligible

          -  Prior organ transplantation including allogenic stem cell transplantation

          -  Diagnosis of myelodysplastic syndrome (MDS)

          -  Vaccination within 4 weeks of study enrollment and while on trial is prohibited except
             for the administration of inactivated vaccines

          -  Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
             accident/stroke (< 6 month prior to enrollment), myocardial infarction (< 6 months
             prior to enrollment), unstable angina, congestive heart failure (>= New York Heart
             Association Classification class II) or a serious cardiac arrhythmia requiring
             medication

          -  Other acute or chronic medical or psychiatric conditions including but not limited to
             recent (within the past year) or active suicidal ideation or behavior or laboratory
             abnormality that may increase the risk associated with study participation or
             investigational product administration or may interfere with the interpretation of
             study results, and in the judgement of the Investigator, would make the patient
             inappropriate for entry into this study

          -  Pregnant female patients, breastfeeding female patients, fertile male patients, and
             female patients of childbearing potential who are unwilling or unable to use 2 highly
             effective methods of contraception as outlined in this protocol for the duration of
             the study, and for at least 30 days after the last dose of avelumab and at least 60
             days after the last dose of M6620 or M3814, whichever is later for the individual
             patient

          -  Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive
             HBV surface antigen or HCV ribonucleic acid (RNA) if anti-HCV antibody screening test
             is positive)

          -  Known history of testing positive for human immunodeficiency virus (HIV) or known
             acquired immune deficiency syndrome (AIDS)

          -  Known additional malignancy that is active and/or progressive requiring treatment;
             exceptions include basal cell or squamous cell skin cancer, in situ bladder cancer, or
             other cancer for which the patient has been disease-free for >= 2 years

          -  Persisting toxicity related to prior therapy (NCI CTCAE v4 grade > 1); however,
             alopecia and sensory neuropathy grade =< 2, or other grade =< 2 AEs not constituting a
             safety risk, based on the investigator's judgement, are acceptable

          -  Subjects receiving treatment with strong inhibitors or inducers of CYP3A4 that cannot
             be discontinued before start of investigational treatment and for the duration of
             study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Limiting Toxicity (DLT) (i.e. Number of patients with dose limiting toxicities as assessed by CTCAE v5.0)
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Clinical benefit rate
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:Will estimate the clinical benefit rate separately for each arm with appropriate 95% confidence intervals.
Measure:Response rate
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:Will estimate the response rate separately for each arm with appropriate 95% confidence intervals.
Measure:Progression free survival (PFS)
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:Will also estimate the PFS using Kaplan-Meier methods.
Measure:Overall survival (OS)
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:Will also estimate the OS using Kaplan-Meier methods.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

February 10, 2020