MC# 18-23 - A Phase 2, Open-label, Multicenter, Study of an Immunotherapeutic Treatment, DPX-Survivac in combination with Low Dose Cyclophosphamide and Pembrolizumab, in Subjects with Selected Advanced and Recurrent Solid Tumours.

  • Agent(s): DPX-Survivac
  • Disease Type(s): Solid Tumor, Lung-NSCLC, Ovarian, Hepatocellular, Breast
  • Phase(s): II
  • Drug Classification(s): Targeted Therapy, Immunotherapy
  • Molecular Target(s): Survivin

Mechanism of Action

DPX-Survivac is an immunotherapeutic treatment that targets survivin, a cancer stem cell antigen and biomarker of cancer progression, to initiate apoptosis. This will be used in combination with a cytotoxic drug.

Purpose

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

  • The effects of the study drug (good and bad) when given in combination with Pembrolizumab, with or without Cyclophosphamide
  • How your body’s immune system reacts to the study drug regimen
Inclusion Criteria
  • Willing and able to provide informed consent for the trial.
  • Adults of at least 18 years of age on day of signing consent.
  • Subjects with advanced or metastatic solid tumours who have disease progression after treatment with all available therapies for metastatic disease that are known to confer clinical benefit, are intolerant to treatment, or refuse standard treatment. There is no limit to the number of prior treatment regimens; subjects may be classified as resistant or sensitive to their last platinum-based chemotherapy, not refractory.
    • OvCa: Epithelial ovarian, fallopian tube, or peritoneal cancer with histologic documentation of the original primary tumour via pathology report; any histology within epithelial is acceptable. Carcino-sarcoma will not be considered epithelial and are therefore excluded.
    • HCC: Hepatocellular carcinoma with histological documentation from the original biopsy (non- cirrhotic subjects) or clinical diagnosis by American Association for the Study of Liver Disease (AASLD) criteria (cirrhotic subjects).
    • NSCLC: Histologically or cytologically confirmed non-small cell lung cancer.
    • BlCa: Histologically confirmed urothelial cancer (including urinary bladder, ureter, urethra, and renal pelvis).
    • MSI-H: Microsatellite instability high solid tumours, other than the above indications. Microsatellite instability must be confirmed using archival tumour tissue.
  • Checkpoint inhibitor naïve or prior exposure to anti–CTLA4, anti–PD-1/L1 mAb is allowed. Enrolment of subjects who have been previously exposed to anti-PD-1/L1 or CTLA4 will be capped to 50% of subjects in each cohort/arm.
    • Prior exposure is defined as having received at least 2 doses of an anti-PD-1/L1 or CTLA4 mAb
    • Confirmed response to prior exposure, as defined by RECIST v1.1, must be available
  • Radiologic and/or biochemical evidence of disease progression.
  • Completion of a pre-treatment tumour biopsy.
    • Subjects with HCC, NSCLC, BlCa, or MSI-H subjects other than those with gastric or colorectal cancer must have evidence of survivin expression in their pre-treatment biopsy sample.
    • If a pre-treatment biopsy is considered unsafe the subject may still be eligible following discussion with the Medical Monitor, provided an archived biopsy sample is available for study assessments.
    • Submission of formalin-fixed paraffin embedded tumour tissue sample blocks are preferred; if submitting unstained slides, the slides should be freshly cut and submitted to the testing laboratory within 14 days from site slide sectioning date otherwise a new specimen will be requested.
  • Have measurable disease per RECIST 1.1 as assessed by the central imaging. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
  • Ambulatory with an Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
  • Life expectancy ≥ 6 months.
  • Have adequate organ function as defined in the following table:

System

Laboratory Value

Hematological

 

Absolute neutrophil count (ANC)

≥ 2,500/mcL

Platelets

≥ 100,000/mcL

Hemoglobin

≥ 9.0 g/dL or ≥ 5.6 mmol/L3

Renal

 

Creatinine OR

Measured or calculated4 creatinine clearance

 GFR can also be used in place of creatinine or CrCl

≤1.5 × ULN OR ≥30 mL/min for subject with creatinine levels > 1.5 × institutional ULN

Hepatic

 

Total bilirubin

≤ 1.5 × ULN OR

Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 × ULN

AST (SGOT) and ALT (SGPT)

≤ 2.5 × ULN (≤ 5 × ULN for subjects with liver metastases)

Coagulation

 

International normalized ratio (INR) OR Prothrombin time (PT)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

ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.

3 Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last two weeks

4 Creatinine clearance (CrCl) should be calculated per institutional standard.

 

  • A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
    • Not a woman of childbearing potential (WOCBP)
    • A WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 150 days after the last dose of study treatment.
  • A male subject must agree to use contraception during the treatment period and for at least 210 days after the last dose of study treatment.
  • Ability to comply with protocol requirements.
Exclusion Criteria

Cancer Treatment Exclusions

  • Chemotherapy or immunotherapy treatment within 28 days of day 0.
    • Subjects must have recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline. Subjects with ≤ Grade 2 neuropathy may be eligible.
    • If a subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
  • Receipt of prior radiotherapy within 2 weeks of start of study treatment. Must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1- week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
  • Prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T cell receptor (e.g., CTLA-4, OX40, CD137) where subject was discontinued from that treatment due to a Grade 3 or higher immune-related toxicity (irAE).
  • Prior receipt of investigational immune therapy (other than those above-mentioned) must be discussed with the medical monitor to determine eligibility.
  • Prior receipt of survivin-based treatment(s).

Co-Morbidity Exclusions

  • Concurrent (within the last 5 years) additional malignancy.
    • Basal cell carcinoma or squamous cell carcinoma of the skin, cervical carcinoma in situ, or controlled bladder cancer* that have undergone potentially curative therapy are not exclusionary (*only subjects enrolled to cohorts other than BlCa may have had concurrent controlled bladder cancer).
  • Clinical ascites that cannot be managed or metastatic pleural fluid.
    • Symptomatic or large volume ascites that can be removed prior to study day 0 is not exclusionary.
    • Asymptomatic or small volume ascites is not exclusionary.
    • Pleural fluid that is only visible by radiologic imaging and is not due to disease progression is not exclusionary.
  • Malignant bowel obstruction or recent history of bowel obstruction that might jeopardize the subject ability to receive treatment (OvCa).
  • For OvCa, subjects with any single lesion greater than 5 cm will be excluded.
  • Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
    • Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
  • Any history of (non-infectious) pneumonitis that required steroid therapy or current pneumonitis.
  • Has an active infection requiring systemic therapy.
  • Presence of a serious acute infection requiring antibiotic treatment within 28 days of day 0.
  • Chronic infection including but not limited to: urinary tract infection, syphilis (Treponema pallidum), human immunodeficiency virus (HIV) infection, or a known history of Hepatitis B or known active Hepatitis C virus infection.
    • No HIV testing is required unless mandated by local health authority.
    • No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority. Hepatitis B is defined as Hepatitis B surface antigen [HBsAg] reactive. Active Hepatitis C defined as HCV RNA [quantitative] is detected.
    • Subjects with a known history of Hepatitis C who have undergone curative treatment will not be excluded.
    • A positive test result for latent tuberculosis is not exclusionary however enrolled subjects must undergo prophylactic treatment.
  • Has known active CNS metastases and/or carcinomatous meningitis.
    • Subjects with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
  • GI condition that might limit absorption of oral agents.
  • Has had an allogenic tissue/solid organ transplant
  • Myocardial infarction or cerebrovascular event within 6 months (168 days) of day 0.
  • Serious intercurrent chronic or acute illness, such as cardiac disease (New York Heart Association class III or IV), hepatic disease (other than HCC related symptoms for HCC cohort), or other illness considered by the investigator as an unwarranted high risk for an investigational product.
  • History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

Co-Medication Exclusions

  • Has received a live vaccine within 30 days prior to first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
  • Long term-use of therapeutic doses of systemic steroids or other immunosuppressive, such as azathioprine or cyclosporin A. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
    • Subjects who have discontinued any steroids at least 21 days prior to day 0 (except that used as pre-medication for chemotherapy or contrast-enhanced studies) may be eligible.
    • Short term use of steroids for asthma or chronic obstructive pulmonary disorder (COPD) exacerbation and topical steroids are acceptable.
  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
    • Subjects who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.

Patient Safety Exclusions

  • Acute or chronic skin and/or microvascular disorders that will interfere with subcutaneous injection of DPX-Survivac or subsequent assessment of potential skin reactions.
  • Edema or lymphedema in the lower limbs > Grade 2.
  • Known allergies to DPX-Survivac components.
  • Known allergy or reaction to any component of cyclophosphamide.
  • Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients.
  • A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  • Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 150 days (for women) and 210 days (for men) after the last dose of study treatment.
  • Medical or psychological impediment to probable compliance with the protocol.
  • Has a known psychiatric or substance abuse disorder that would interfere with the subject’s ability to cooperate with the requirements of the study.

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City

Contact Us About This Trial

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Re: MC# 18-23