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

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ClinicalTrials.gov Identifier: NCT04266912
Recruitment Status : Not yet recruiting
First Posted : February 12, 2020
Last Update Posted : March 24, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Advanced Malignant Solid Neoplasm Metastatic Malignant Solid Neoplasm Unresectable Malignant Solid Neoplasm Drug: ATR Kinase Inhibitor M6620 Drug: Avelumab Drug: Nedisertib Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 66 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Estimated Study Start Date : March 31, 2020
Estimated Primary Completion Date : September 11, 2024
Estimated Study Completion Date : September 11, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Avelumab

Arm Intervention/treatment
Experimental: Arm A (avelumab, ATR kinase inhibitor M6620)
Patients 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.
Drug: ATR Kinase Inhibitor M6620
Given IV
Other Names:
  • M 6620
  • M6620
  • VX-970

Drug: Avelumab
Given IV
Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C

Experimental: Arm B (avelumab, nedisertib)
Patients 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.
Drug: Avelumab
Given IV
Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C

Drug: Nedisertib
Given PO
Other Names:
  • 3-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
  • MSC2490484A




Primary Outcome Measures :
  1. 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 ]
  2. 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. [ Time Frame: Up to 1 year post treatment ]
  3. Maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of MM3814 and avelumab in patients with DDR deficient advanced solid tumors. [ Time Frame: Up to 1 year post treatment ]

Secondary Outcome Measures :
  1. Clinical benefit rate [ Time Frame: Up to 1 year post treatment ]
    Will estimate the clinical benefit rate separately for each arm with appropriate 95% confidence intervals.

  2. Response rate [ Time Frame: Up to 1 year post treatment ]
    Will estimate the response rate separately for each arm with appropriate 95% confidence intervals.

  3. Progression free survival (PFS) [ Time Frame: Up to 1 year post treatment ]
    Will also estimate the PFS using Kaplan-Meier methods.

  4. Overall survival (OS) [ Time Frame: Up to 1 year post treatment ]
    Will also estimate the OS using Kaplan-Meier methods.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04266912


Contacts
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Contact: Timothy A. Yap 713-563-1930 tyap@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Contact: Timothy A. Yap    713-563-1930      
Principal Investigator: Timothy A. Yap         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Timothy A Yap M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT04266912    
Other Study ID Numbers: 2018-1059
NCI-2019-07598 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2018-1059 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: February 12, 2020    Key Record Dates
Last Update Posted: March 24, 2020
Last Verified: March 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs