Clinical Trials /

Phase Ib/IIa Trial to Evaluate Oregovomab and Nivolumab in Epithelial Cancer of Ovarian, Tubal or Peritoneal Origin

NCT03100006

Description:

The purpose of this study is to characterize the safety and tolerability, identify a recommended dose for expansion (RDE) / recommended phase II dose (RP2D), pharmacodynamics, and antitumor activity of Oregovomab vaccination in combination with Nivolumab as a novel combinatorial immunotherapeutic strategy in in female patients with recurrent epithelial ovarian cancer (EOC) who progressed after two or more prior lines of cytotoxic chemotherapy.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Malignant Ovarian Clear Cell Tumor
  • Malignant Ovarian Serous Tumor
  • Ovarian Carcinoma
  • Ovarian Endometrioid Tumor
  • Ovarian Mixed Epithelial Tumor
  • Ovarian Mucinous Tumor
  • Primary Peritoneal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase Ib/IIa Trial to Evaluate Oregovomab and Nivolumab in Epithelial Cancer of Ovarian, Tubal or Peritoneal Origin
  • Official Title: A Phase Ib/IIa Clinical Trial to Evaluate the Safety and Activity of Oregovomab and Nivolumab as a Combinatorial Immunotherapy Strategy in Patients With Recurrent Epithelial Cancer of Ovarian, Tubal or Peritoneal Origin

Clinical Trial IDs

  • ORG STUDY ID: NCC OV-02
  • NCT ID: NCT03100006

Conditions

  • Epithelial Ovarian Cancer

Interventions

DrugSynonymsArms
NivolumabOpdivoNivolumab and Oregovomab
OregovomabOvaRexNivolumab and Oregovomab

Purpose

The purpose of this study is to characterize the safety and tolerability, identify a recommended dose for expansion (RDE) / recommended phase II dose (RP2D), pharmacodynamics, and antitumor activity of Oregovomab vaccination in combination with Nivolumab as a novel combinatorial immunotherapeutic strategy in in female patients with recurrent epithelial ovarian cancer (EOC) who progressed after two or more prior lines of cytotoxic chemotherapy.

Detailed Description

      This study tests the hypothesis that the combination of Oregovomab and Nivolumab will improve
      intracellular Cancer Antigen (CA) 125 antigen processing and elicit a stronger systemic CA
      125-specific T cell response; in a manner that is synergistic, safe, and clinically
      efficacious in patients with relapsed EOC.

      This is an open-label, single-arm, phase Ib/IIa, single-center study with dose finding and
      dose expansion parts.

      In the phase Ib part, clinically recommended doses as monotherapy for Oregovomab (IV 2 mg
      Q4W, dose level 1) and Nivolumab (IV 240 mg Q2W) will be the starting doses for their
      combined use.

      A modified "3+3" dose finding design will be employed, with 2 lower dosages of Oregovomab
      (dose level -1 at 1 mg Q4W; level -2 at 0.5 mg Q4W) specified in case of excessive toxicity
      (defined as ≥ 2 dose limiting toxicities (DLTs) out of first 3 patients, or all 6 patients)
      encountered at dose level 1. Three patients will be initially enrolled into dose level 1. If
      0 or 1 DLT is observed, another 3 patients will be enrolled into the same dose level;
      otherwise de-escalate and enroll 3 patients at dose level -1. If ≤ 1 DLT is observed among
      the 6 patients, dose level 1 will be the RDE/RP2D of Oregovomab to be combined with
      Nivolumab. Likewise, in the event of de-escalation, if 0 or 1 DLT is observed at a lower dose
      level, a further 3 patients will be enrolled for that level; if ≤ 1 DLT is observed out of
      the 6 patients, that dose level will be the RDE/RP2D.

      A minimum of 6 and a maximum of 18 patients will be enrolled in the dose finding part.

      Approximately 14 patients are to enroll in the dose expansion part wherein they will receive
      Oregovomab at RDE/RP2D, combined with Nivolumab. In total, 20 patients from the dose finding
      and dose expansion cohorts will be treated at RDE/RP2D, and be included in the phase IIa
      study population.

      Patients will be followed up for survival and post-progression treatment(s) over a duration
      of up to 36 months from the time of treatment initiation (i.e., Week 0 until up to 36
      months).
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab and OregovomabExperimental
  • Nivolumab
  • Oregovomab

Eligibility Criteria

        Inclusion Criteria:

          1. Signed Written Informed Consent

               -  Able to understand and voluntarily sign the Informed Consent Form (ICF). Written
                  informed consent must be obtained before any study specific procedures that are
                  not part of standard of care.

               -  Willing and able to comply with scheduled visits, treatment schedule, laboratory
                  test, and other protocol requirements

          2. Age and Target Population

             • Age ≥ 21 years old

               -  Histologically and/or cytologically confirmed diagnosis of epithelial ovarian
                  carcinoma (serous, clear cell, endometrioid, mucinous, mixed, and others),
                  fallopian tube and primary peritoneal carcinoma

               -  Serum CA 125 level at enrollment must be at least twice the upper limit of normal
                  (ULN) using local laboratory ranges

               -  Objective evidence of disease recurrence following initial curative-intent
                  treatment, and of progression after at least 2 prior lines of cytotoxic
                  chemotherapy (including platinum and taxane) for advanced stage disease. Patients
                  may have received prior treatment with Bevacizumab.

               -  Presence of:

                  (a) measurable disease as defined by RECIST v1.1 AND a pre-treatment serum CA 125
                  level ≥ 2 x ULN on 1 occasion, OR (b) non-measurable but evaluable disease such
                  as ascites and pleural effusions attributable to disease or radiologic
                  abnormalities that do not meet RECIST v1.1 criteria AND a pre-treatment serum CA
                  125 level ≥ 2 x ULN on 2 occasions at least 1 week apart, OR (c) non-evaluable,
                  non-measurable disease as defined by RECIST v1.1 AND pre-treatment CA 125 level ≥
                  2 x ULN on 2 occasions at least 1 week apart

               -  Estimated life expectancy greater than 3 months

               -  Performance status Eastern Cooperative Oncology Group (ECOG) 0 or 1

               -  Adequate hematologic and end organ function, defined by the following local
                  laboratory results obtained within 14 days before study entry:

                    1. Absolute Neutrophil Count (ANC) ≥ 1.5 × 109/L (without granulocyte
                       colony-stimulating factor support within 2 weeks of laboratory test used to
                       determine eligibility)

                    2. White Blood Cells (WBC) count ≥ 2.0 × 109/L

                    3. Platelet count ≥ 100 × 109/L (without transfusion within 2 weeks of
                       laboratory test used to determine eligibility)

                    4. Hemoglobin ≥ 9.0 g/dL (Patients may be transfused or receive erythropoietic
                       treatment to meet this criterion)

                    5. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 30 ml/min
                       according to Cockcroft-Gault formula below:

                       Female CrCl = [(140 - age in years) x weight in kg x 1.04]/serum creatinine
                       in mmol/L

                       Male CrCl = [(140 - age in years) x weight in kg x 1.23]/ serum creatinine
                       in mmol/L

                    6. AST and ALT ≤ 3 × ULN (or ≤ 5 × ULN in patients with liver metastases)

                    7. Serum bilirubin ≤ 1.5 × ULN (except patients with known Gilbert's disease
                       who have serum bilirubin level ≤ 3 × ULN)

               -  Recovery of acute AEs of prior anticancer therapies, including surgery and
                  radiotherapy, to baseline or CTCAE grade ≤ 1 before study entry.

                    -  Patients with toxicities attributed to prior anticancer therapy that either
                       are not expected to resolve and/or can result in long-lasting sequelae, such
                       as peripheral neuropathy and ototoxicity of CTCAE grade ≤ 2 after
                       platinum-based therapy, or are not expected to interfere with treatment on
                       study, such as alopecia, are eligible.

          3. Reproductive Status

               -  Women of childbearing potential (WOCBP) must have a negative urine pregnancy test
                  (minimum sensitivity 25 IU/L or equivalent units of hCG) within 14 days before
                  study entry.

               -  No breastfeeding

               -  WOCBP must agree to observe abstinence from heterosexual sexual intercourse, or
                  use contraceptive methods that results in a failure rate of < 1% per year during
                  the treatment period and for 5 half-lives of Nivolumab (half-life up to 25 days)
                  plus 30 days (duration of ovulatory cycle) for a total of 23 weeks after the last
                  IP administration. The investigator or a designated associate is requested to
                  advise the subject on how to achieve adequate birth control.

                    -  A woman is considered to be of childbearing potential if she has not reached
                       a postmenopausal state (≥ 12 consecutive months of amenorrhea with no
                       identified cause other than menopause), and has not undergone surgical
                       sterilization (bilateral oophorectomy with or without hysterectomy, or
                       bilateral tubal ligation).

                    -  Examples of contraceptive methods with a failure rate of < 1% per year
                       include bilateral tubal ligation, male sterilization, properly used hormonal
                       contraceptives that inhibit ovulation (stable on the same pill for minimum
                       of 3 months before study entry), hormone-releasing intrauterine devices, and
                       copper intrauterine devices.

        Exclusion Criteria:

          1. Cancer-specific Exclusions

             • Non-epithelial ovarian tumors, including malignant mixed Müllerian tumors
             (carcinosarcoma), or ovarian tumors with low malignant potential (i.e., borderline
             tumors).

               -  Active symptomatic central nervous system (CNS) metastases. Patients with
                  previous CNS metastases are eligible provided that they underwent CNS
                  irradiation, are asymptomatic, do not require treatment with radiation therapy or
                  anticonvulsants, and have stable disease at the screening tumor assessment. In
                  addition, these patients must have been either off corticosteroids, or on a
                  stable or decreasing dose of ≤ 10 mg daily prednisolone (or equivalent).

               -  Spinal cord compression not definitively treated with surgery and/or radiation.
                  Patients with previously diagnosed and treated spinal cord compression are
                  eligible provided that they have stable disease at the screening tumor
                  assessment. In addition, these patients must have been either off
                  corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisolone
                  (or equivalent).

               -  Leptomeningeal carcinomatosis

               -  Uncontrolled pleural effusion(s), pericardial effusion, or ascites requiring
                  recurrent drainage procedures

                  o Patients with functioning pleural and/or peritoneal drainage catheters/devices
                  in situ at time of study entry may be eligible.

               -  Previous malignancies (except non-melanoma skin cancers, and the following in
                  situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma,
                  or breast) unless a complete remission was achieved at least 2 years before study
                  entry AND no additional therapy is required, or anticipated to be required,
                  during the study period.

          2. General Medical Exclusions

               -  Pregnant or lactating women

               -  Evidence of significant uncontrolled concomitant disease that could affect
                  compliance with the protocol or interpretation of results, including significant
                  liver disease such as cirrhosis, uncontrolled major seizure disorder, or superior
                  vena cava syndrome

               -  Significant cardiovascular disease, such as New York Heart Association cardiac
                  disease (Class II or greater), myocardial infarction within 3 months before study
                  entry, unstable arrhythmias/heart block, or unstable angina

                  o Patients with a known left ventricular ejection fraction (LVEF) < 40% or
                  pre-existing poorly controlled hypertension (systolic blood pressure > 160 mmHg
                  or diastolic pressure > 90 mmHg despite optimal medical management) will be
                  excluded.

                    -  Patients with known coronary artery disease, congestive heart failure not
                       meeting the above criteria, or LVEF < 50% must be on a stable medical
                       regimen that is optimized in the opinion of the treating physician, in
                       consultation with a cardiologist if appropriate.

                    -  Patients with stable cardiac arrhythmia requiring stable dose(s) of
                       anti-arrhythmic therapy may be eligible.

               -  Severe infections within 4 weeks before study entry including but not limited to
                  hospitalization for complications of infection, bacteremia, or severe pneumonia

               -  Significant traumatic injury, or major surgical procedure within 4 weeks before
                  study entry, or anticipation of need for a major surgical procedure during the
                  course of the study other than for diagnosis

               -  History of abdominal fistula, history of gastrointestinal perforation, and signs
                  or symptoms of bowel obstruction

               -  Symptoms or radiological evidence of active bowel obstruction

               -  Non-healing wound or ulcer, or bone fracture within 3 months before study entry.

               -  Systemic anticancer therapy during the study, or before study entry as follows:

                  (a) Cytotoxic chemotherapy: greater than the duration of the most recent cycle of
                  the previous regimen, with a minimum of 6 weeks for nitrosoureas and mitomycin-C
                  and a minimum of 2 weeks for all others

                  (b) Biologic therapy (e.g., antibodies): up to 2 weeks

                  (c) Endocrine therapy: Fulvestrant 4 weeks; Tamoxifen 2 weeks; aromatase
                  inhibitors 2 weeks

                  (d) Continuous or intermittent small molecule therapeutic: 5 times the half-life
                  (if known), with a minimum of 2 weeks

                  (e) Immunostimulatory agent (including but not limited to interferons,
                  interleukin-2 or other cytokines): 4 weeks or 5 times the half-life (if known),
                  whichever is shorter

                    -  Patients who have not recovered from therapy-related toxicities, except
                       alopecia, peripheral neuropathy and ototoxicity (CTCAE grade ≤ 2), to
                       baseline or CTCAE grade ≤ 1 are also excluded.

               -  Extended field radiotherapy within 4 weeks, or limited field radiotherapy within
                  2 weeks before study entry. Patients who have not recovered from therapy-related
                  toxicities to baseline or CTCAE grade ≤ 1 are also excluded. The site of previous
                  radiotherapy should have evidence of progressive disease if this is the only site
                  of disease.

               -  Seizure disorder requiring anti-epileptic medication

               -  Renal failure requiring hemo- or peritoneal dialysis

               -  Known medical condition that, in the investigator's opinion, would increase the
                  risk associated with study participation or administration of Investigational
                  Products (IPs), or interfere with the interpretation of safety results

               -  Substance abuse, medical, psychological or social conditions that may interfere
                  with the patient's participation in the study or evaluation of the study results

          3. Exclusions Related to Investigational Products

             • Other concurrent/ongoing systemic investigational agents

               -  Previous assignment to treatment during this study. Subjects permanently
                  withdrawn from study treatment participation will not be allowed to re-enter the
                  study.

               -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
                  murine or humanized antibodies or fusion protein

               -  Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese
                  hamster ovary cell products or any component of the IPs

               -  Prior therapy with anti-CA 125 cancer vaccine, or anti-PD-1, anti-PD-L1,
                  anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including any other antibody or
                  immunotherapeutic drug specifically targeting T cell co-stimulation or checkpoint
                  pathways)

               -  Active, known or suspected autoimmune disease including but not limited to
                  myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus,
                  rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated
                  with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome,
                  Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
                  Subjects with an autoimmune paraneoplastic syndrome requiring concurrent
                  immunosuppressive treatment are excluded.

                    -  Patients with controlled Type 1 diabetes mellitus, autoimmune thyroid
                       disorders who are currently euthyroid or with residual hypothyroidism only
                       requiring hormone replacement, skin disorders (e.g., vitiligo, psoriasis or
                       alopecia) not requiring systemic treatment, or conditions not expected to
                       recur in the absence of an external trigger may be eligible.

               -  Active use of systemic corticosteroids (≥ 10mg/day prednisolone or equivalent) or
                  other systemic immunosuppressive agents (including but not limited to
                  prednisolone, dexamethasone, cyclophosphamide, azathioprine, methotrexate,
                  thalidomide, and anti-tumor necrosis factor [TNF] agents) within 2 weeks before
                  study entry, or anticipated requirement for systemic immunosuppressive
                  medications during the study.

                    -  Patients who have received acute, low dose, corticosteroid medications
                       (e.g., a one-time dose of dexamethasone for nausea) may be eligible.
                       Replacement-dose steroids in the setting of adrenocortical insufficiency
                       (provided this is ≤ 10mg/day prednisolone or equivalent) is permitted.

                    -  The use of topical, inhaled, nasal and ophthalmic corticosteroids and
                       systemic mineralocorticoids (e.g., fludrocortisone) is allowed.

               -  History of solid organ allograft or allogeneic hematopoietic stem cell
                  transplantation

               -  Pre-existing Human Immunodeficiency Virus (HIV) infection, Acquired Human
                  Immunodeficiency Syndrome (AIDS) or chronic hepatitis C infection. Patients with
                  past hepatitis B virus (HBV) infection or resolved HBV infection (defined as
                  having a negative hepatitis B surface antigen [HBsAg] test and a positive
                  antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible.
                  Patients with hepatitis B (HBV) infection (defined as having a positive HBsAg
                  test) AND undetectable HBV DNA titer are also eligible.

                  o HBV DNA must be obtained in these patients before study entry. The use of
                  antiviral therapy to attain virological response (i.e., undetectable HBV DNA
                  titer) in HBV-infected patients is permitted.

               -  Active tuberculosis

               -  Administration of a live, attenuated vaccine within 4 weeks before study entry,
                  or anticipation that such a live attenuated vaccine will be required during the
                  study

               -  Interstitial lung disease that is symptomatic or may interfere with the detection
                  and management of suspected drug-related pulmonary toxicity.

          4. Other Exclusions Criteria

               -  Inability to attend or comply with treatment of follow-up scheduling
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:21 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of incidences and severity of Adverse Events (AE) and Serious AEs that are treatment-related, graded based on the CTCAE v4.03
Time Frame:4 weeks from the start of treatment
Safety Issue:
Description:The proportion of patients with a best overall response of Complete Response (CR) or Partial Response (PR)

Secondary Outcome Measures

Measure:ORR as per immune-related response criteria (irRC)
Time Frame:Time from date of start of treatment until best overall response of CR or PR, up to 3 years
Safety Issue:
Description:The proportion of patients with best overall response of CR or PR
Measure:Disease control rate (DCR) as per GCIG criteria and irRC
Time Frame:Time from date of start of treatment until best overall response of CR, PR or SD, up to 3 years
Safety Issue:
Description:The proportion of patients with best overall response of CR, PR or Stable Disease (SD)
Measure:ORR in EOC subtypes
Time Frame:Time from date of start of treatment until best overall response of CR or PR, up to 3 years
Safety Issue:
Description:High Grade Serous, Clear Cell, Endometrioid, Mucinous, Mixed, Others and BRCA1/2 tumors
Measure:Overall survival (OS) as per GCIG criteria
Time Frame:Time from date of start of treatment to date of death due to any cause, up to 3 years
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Centre, Singapore

Last Updated

September 13, 2018