MC# 21-01 - A Phase Ib, Multicenter, 2-Part, Open-Label Study of DS-1062a in Combination with Durvalumab in Subjects with Advanced or Metastatic Non-Small Cell Lung Cancer without Actionable Genomic Alterations and Previously Treated with Platinum-based Chemotherapy with or without Prior Immunotherapy (DS1062-A-U104)

  • Agent(s): DS-1062a
  • Disease Type(s): Lung-NSCLC
  • Phase(s): I
  • Drug Classification(s): Antibody Drug Conjugate
  • Molecular Target(s): TROP2

Mechanism of Action

DS-1062a targets and binds to TROP2 expressed on tumor cells.  Upon cellular uptake and lysosomal degradation of the linker, DXd targets and binds to DNA topoisomerase I, thereby stabilizing the cleavable complex between topoisomerase I and DNA, resulting in DNA breaks, inhibition of DNA replication and apoptosis.  This inhibits tumor cell proliferation of TROP2-expressing tumor cells.

Purpose

In this study, the sponsor and investigators want to learn:

  • If DS-1062a in combination with Durvalumab prevents or delays tumor growth or shrinks existing tumors
  • About the safety and tolerability of DS-1062a in combination with Durvalumab
  • How proteins that indicate the status of your disease are affected with use of DS-1062a and Durvalumab
  • How quickly DS-1062a and Durvalumab is removed from your bloodstream
  • If research tests can be used in the future to predict who will benefit from DS-1062a
Inclusion Criteria
  1. Sign and date the ICF, prior to the start of any study-specific qualification procedures
  2. Adult ≥18 years of age in the United States or ≥20 years of age in Japan on the day of signing the ICF (if the legal age of consent is >18 years old, then local regulatory requirements to consent should be followed)
  3. Histologically confirmed diagnosis of NSCLC that:
    1. Is advanced or metastatic
    2. Has documented negative test results for EGFR and ALK genomic alterations.  If documented negative test results for EGFR and ALK are not available, subjects are required to have testing performed locally for these genomic alterations.
    3. Has no known genomic alterations in ROS1, NTRK, BRAF, or other driver oncogenes with approved therapies (actionable genomic alterations)

Note that subjects with mixed small cell lung cancer (SCLC)/NSCLC histology are not eligible

  1. Has documentation of radiological disease progression while on or after receiving the most recent treatment regimen for advanced or metastatic NSCLC
  2. Must meet the following prior therapy requirements for advanced or metastatic NSCLC:
    1. Has received at least 1 regimen of platinum-based chemotherapy and
    2. Has at least 1 regimen of PD-1/PD-L1 directed immunotherapy, either in combination or sequentially.  Subjects with a documented PD-L1 TPS of <1% must have been previously treated with at least 1 regimen of platinum-based chemotherapy with or without prior PD-1/PD-L1 immunotherapy.

Subjects who meet these prior therapy requirements and who may have received additional lines of therapy are also eligible.

  1. Willing and able to undergo a mandatory tumor biopsy for the measurement of TROP2 expression levels and for assessment of other biomarkers.  If available, a tumor biopsy that was recently collected (within 3 months of screening) after completion of the most recent anticancer treatment regimen and that has a minimum of 10 sections at 4 microns or a tissue block equivalent of 10 sections at 4 microns may be substituted for the biopsy collected during screening.  Results of TROP2 testing of the pretreatment tumor biopsy will not be used to determine the eligibility for the study.  PD-L1 level will not be used for inclusion.  The screening biopsy should only be collected after all other eligibility criteria are met.
  2. Archival tumor tissue from initial diagnosis is required, to the extent that archival tumor tissue is available, for measurement of TROP2 expression levels or other biomarkers
  3. Has measurable disease based on local imaging assessment using RECIST Version 1.1.  Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.  Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to Cycle 1 Day 1.
  4. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at screening
  5. Adequate bone marrow reserve and organ function within 7 days prior to Cycle 1 Day 1, defined as:

Parameter

Laboratory Value

Adequate Bone Marrow Function

Platelet Count

Platelet count ≥100,000/mm3 (platelet transfusion is not allowed within 1 week prior to screening assessment) 

Hemoglobin (Hgb)

Hemoglobin ≥9.0 g/dL (red blood cell/plasma transfusion is not allowed within 1 week prior to screening assessment)

Absolute Neutrophil Count (ANC)

Absolute neutrophil count ≥1500/mm3 (granulocyte-colony stimulating factor [G-CSF] administration is not allowed within 1 week prior to screening assessment).

Adequate Renal Function

Creatinine Clearance (CrCl)

CrCl >40 mL/min, as calculated using the Cockcroft-Gault equationa (using actual body weight in kg)

Adequate Hepatic Function

Alanine Aminotransferase (ALT)/Aspartate Aminotransferase (AST)

ALT and AST ≤2.5 × upper limit of normal (ULN); for subjects with hepatic metastases, ALT and AST ≤5 × ULN

Total bilirubin

≤1.5 × ULN if no liver metastases or <3 × ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline

Adequate Blood Clotting Function

International normalized ratio (PT-INR)/Prothrombin time

(PT) and either partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT)

≤1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants

a Cockcroft-Gault equation: CrCl (mL/min) =  [140 - age (years)] × weight (kg)] ÷[ 72 × serum creatinine (mg/dL)] {× 0.85 for female subjects}

  1. Adequate treatment washout period before Cycle 1 Day 1, defined as:

Treatment

Washout Period

Major surgery

≥4 weeks

Radiation therapy, including palliative radiation to chest

≥4 weeks (palliative radiation therapy to other areas ≥2 weeks)

Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation

≥4 weeks

Anticancer chemotherapy (Immunotherapy [non-antibody-based therapy]), retinoid therapy

≥2 weeks or 5 times the terminal elimination half-life (t1/2) of the chemotherapeutic agent, whichever is longer; ≥6 weeks  for nitrosoureas or mitomycin C), ≥1 week for TKIs approved for the treatment of NSCLC - baseline CT scan must be completed after discontinuation of TKI

Antibody-based anticancer therapy

≥4 weeks

Chloroquine/ Hydroxychloroquine (CQ/HCQ)

>14 days

  1. Within 28 days before Cycle 1 Day 1, have left ventricular ejection fraction (LVEF) ≥50% by either an ECHO or MUGA
  2. If male, the subject must be surgically sterile or must agree to use highly effective birth control upon enrollment, during the Treatment Period, and for at least 4 months following the last dose of study treatment
  3. If the subject is a female of childbearing potential, she must have a negative serum pregnancy test at screening and must be willing to use highly effective birth control, upon enrollment, during the Treatment Period, and for 7 months following the last dose of study treatment.  Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating hormone [FSH] >40 mIU/mL and estradiol <40 pg/mL [<147 mol/L] is confirmatory).  Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for females of childbearing potential if they wish to continue their HRT during the study.  Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status prior to study enrollment.  For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT.  Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
  4. Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and for at least 4 months after the final study treatment administration.  Preservation of sperm should be considered prior to enrollment in this study.
  5. Female subjects must not donate or retrieve, for their own use, ova from the time of screening and throughout the study Treatment Period, and for at least 7 months after the final study treatment administration.  Preservation of ova should be considered prior to enrollment in this study.
  6. Life expectancy of ≥3 months
  7. Body weight >30 kg
Exclusion Criteria
  1. History of allogeneic organ transplantation
  2. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]).  The following are exceptions to this criterion:
    1. Subjects with vitiligo or alopecia
    2. Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
    3. Any chronic skin condition that does not require systemic therapy
    4. Subjects without active disease in the last 5 years may be included but only after consultation with the sponsor
    5. Subjects with celiac disease controlled by diet alone
  3. Uncontrolled or significant cardiac disease including:
    1. Medical history of myocardial infarction or uncontrolled/unstable angina pectoris within 6 months prior to Cycle 1 Day 1
    2. Medical history of symptomatic congestive heart failure (New York Heart Association Class II to IV) or history of serious cardiac arrhythmia requiring treatment
    3. Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) prolongation to >470 ms (females) or >450 ms (males) based on average of the screening triplicate 12-lead ECGs (within 15 minutes at 5 minutes apart)
    4. Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg)
  4. Has other primary malignancies, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated, with no evidence of disease for >5 years and of low potential risk for recurrence
  5. History of leptomeningeal carcinomatosis
  6. History of active primary immunodeficiency
  7. Known human immunodeficiency virus (HIV) infection that is not well controlled.  All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA load, CD4+ counts/levels >250, no history of AIDS-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on same anti-HIV retroviral medications.  If an HIV infection meets the above criteria, monitoring of the subjects’ viral RNA load as well as the CD4+ count levels would be important.  Subjects should be tested for HIV prior to Cycle 1 Day 1 if required by local regulations or institutional review board (IRB)/independent ethics committee (IEC).
  8. Active hepatitis or uncontrolled hepatitis B or C infection; is positive for hepatitis B or C virus based on the evaluation of results of tests for hepatitis B (hepatitis b surface antigen [HBsAg], hepatitis B surface antibody [anti-HBs], hepatitis B core antibody [anti-HBc, or hepatitis B virus [HBV] DNA) or hepatitis C (HCV antibody OR HCV RNA) infection.  Subjects who have received hepatitis B vaccination with only anti-HBs positivity and no clinical signs of hepatitis, and subjects who have been curatively treated for hepatitis C infection as demonstrated clinically and by viral serologies will be eligible.
  9. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia, vitiligo, and the laboratory values defined in the inclusion criteria) not yet resolved to the NCI-CTCAE Version 5.0, Grade ≤1 or baseline.  Subjects with chronic Grade 2 toxicities may be eligible per the discretion of the investigator after consultation with the sponsor medical monitor or designee (eg, Grade 2 chemotherapy-induced neuropathy).  Subjects with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab and DS-1062a may be included only after consultation with the sponsor medical monitor or designee.
  10. Spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.  Subjects with clinically inactive brain metastases may be included in the study.  Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy.  A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment.  Note: A CT or MRI scan of the brain at baseline is required for all subjects.
  11. Known allergy or history of severe hypersensitivity reactions to either the drug substances or inactive ingredients (including but not limited to polysorbate 80)
  12. History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
  13. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (ie, pulmonary emboli within 3 months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc.), or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (ie, rheumatoid arthritis, Sjogren's, sarcoidosis, etc.), or prior pneumonectomy
  14. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.  Note: Subjects with localized fungal infections of skin or nails are eligible.
  15. Clinically significant corneal disease
  16. Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of Cycle 1 Day 1

Note: Inhaled, intranasal, intraocular, intra-articular, or topical steroids and adrenal replacement steroids are permitted in the absence of active autoimmune disease.

  1. Concomitant medical condition that would increase the risk of toxicity, in the opinion of the investigator
  2. History of severe hypersensitivity reactions to other mAbs
  3. Substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject’s participation in the clinical study or evaluation of the clinical study results

Prior and Concomitant Therapy

  1. Receipt of live attenuated vaccine within 30 days prior to the Cycle 1 Day 1

Note: Subjects, if enrolled, should not receive live vaccine while receiving study treatment and up to 30 days after the last dose of study treatment).

  1. Subjects who have received prior anti-PD-1, anti-PD-L1, or anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4):
    1. Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy
    2. All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study
    3. Must not have experienced a Grade ≥3 immune-related AE or an immune-related neurologic or ocular AE of any grade while receiving prior immunotherapy.  Note: Subjects with an endocrine AE of Grade ≤2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
    4. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of >10 mg prednisone or equivalent per day
  2. Current or prior use of immunosuppressive medication within 14 days before Cycle 1 Day 1.  The following are exceptions to this criterion:
    1. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection)
    2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    3. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
  3. Prior treatment with an ADC containing a chemotherapeutic agent targeting Topo I
  4. Previously treated with TROP2-targeted therapy

Prior/Concurrent Clinical Study Experience

  1. Participation in another clinical study with an investigational product administered in the last 4 weeks or 5 times the half-life of the prior investigational product, whichever is longer, prior to Cycle 1 Day 1
  2. Previous study treatment assignment in the present study
  3. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the Follow-up Period of an interventional study
  4. Prior randomization or treatment in a previous durvalumab and/or DS-1062a clinical study regardless of treatment arm assignment

Other Exclusions

  1. Psychological, social, familial, or geographical factors that would prevent regular follow-up
  2. Pregnant or breastfeeding or planning to become pregnant
  3. Judgment by the investigator that the subject should not participate in the study if the subject is unlikely to comply with study procedures, restrictions, and requirements

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://www.clinicaltrials.gov/ct2/show/NCT04612751

Contact Us About This Trial

Reach out to us by sharing your info in the form below or give us a call at 972-566-3000.

Re: MC# 21-01