NorthWest Biotherapeutics Inc (NWBO)

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NWBO is using the DCVax-Direct phase I/II data to look at which endpoints to use for the phase II as yet unannounced independent indication trials. Safety, "Disease control" by causing an immune response and/or any observable tumor response. See Below.

(The CIs (Merck and BMY) chose tumor response, because that got them to approval fastest. Now the CIs must show their PFS/OS medians. The only official one I've seen is for Opdivo on lung cancer. There was no cross-over, and yet they only obtained a 3.1 month advantage. Hopefully the CIs will do better on different indications.)

NWBO stated they enrolled 40 in the phase I version of the current phase I/II trial looking at multiple indications. You know that. However, it is difficult to say how they are handling the transition into the phase II portion of this phase I/II trial beyond those 40 (If any are added). See February 2015 version of the trial protocol summary (60-80 anticipated enrollment). I've received conflicting information on that from various non-company people. So, I just have to be patient.

MDACC Study No: 2013-0160 (clinicaltrials.gov NCT No: NCT01882946)
Title: A Phase I/II clinical trial evaluating DCVax-Direct, autologous activated dendritic cells for intratumoral injection, in patients with solid tumors
Principal Investigator: Vivek Subbiah
Treatment Agent: Dendritic Cells
Study Status: Open
Study Description: The goal of Phase I of this clinical research study is to find the highest
tolerable dose
of DCVax-Direct that can be given to patients with a locally advanced or
metastatic solid tumor cancer.

The goal of Phase II of this study is to learn about the safety of DCVax-Direct
andlearn if it can help to control the disease by causing an immune response
against the
cancer cells. Another goal of this part of the study is to learn if
DCVax-Direct causes any changes to the tumor.

This is the first study using DCVax-Direct in humans.
Hide details for General InformationGeneral Information

Disease Group: Advanced Cancers
Phase of Study: Phase I/Phase II
Treatment Agents: Dendritic Cells
Treatment Location: Both at MDACC & and Other Sites
Estimated Length of Stay in Houston:
Supported By: Northwest Biotherapeutics, Inc.
Return Visit:
Home Care:


Hide details for Study Contact InformationStudy Contact Information

Physician Name: Vivek Subbiah
Dept: Investigational Cancer Therapeutics
For Clinical Trial Enrollment: 713-563-1930
For General Questions about Clinical Trials: 800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)


Hide details for Study Objectives / OutcomesStudy Objectives / Outcomes

Primary

The study contains two phases:

The objective of the first phase is to identify which, if any, of the planned doses can be selected as a maximum tolerated dose (MTD) and collect initial response information in 6 subjects from each of the 6 indications included in the study. At the highest dose, if none of the first 3 subjects experiences a DLT or 1 in the first 6 experience a DLT, the highest dose will be evaluated as the MTD, with the consideration that this dose determination is subject to manufacturing feasibility, such that in effect the optimal dose is highest dose that can be reproducibly manufactured to which these safety considerations apply.

The second phase of the study collects additional doses using the optimal dose as determined in the first phase to:
Confirm the safety at the optimal dose
Evaluate changes in tumor burden and the potential for the observation of tumor response criteria such as RECIST 1.1 and immune response related criteria (IRrC) as well as pathological examination of tumor biopsies.


Secondary
To determine the feasibility of producing and administering DCVax-Direct at 2 million, 6 million or 15 million DC per immunization to eligible subjects with solid tumors;
To identify one or more indications in which to further test DCVax-Direct for efficacy, on the basis of safety, (manufacturing) feasibility, immunogenicity and tumor response/progression;
To determine immune responses to DCVax-Direct (anti-BCG)
To measure anti-tumor immune responses induced by DCVax-Direct;
To evaluate the effects on progression free survival and overall survival using published Phase II data as initial comparator;
To evaluate local effects of DCVax-Direct injections through examination of sequential tumor biopsies at the injection site at the time of each DCVax-Direct injection for tumor necrosis, cellularity, mitotic index, and infiltrating immune- or inflammatory cells (through central pathology).
To evaluate changes in Quality of Life in subjects receiving DCVax-Direct injections;
To evaluate changes in soluble tumor-specific markers in circulation.

Hide details for Study Status InformationStudy Status Information

Study Activation/Registration Date:
IRB Review and Approval Date: 06/18/2013
Study Type: Phase Ii Or Phase I/Ii
Recruitment Status: Open
Projected Accrual: 60 - 80


Hide details for Enrollment EligibilityEnrollment Eligibility

Inclusion Criteria: 1) Age between 18 and 75 years (inclusive) at screening.

2) Karnofsky performance status (KPS) of 70 or higher or ECOG 0-1 at screening.

3) Patients with a histological or cytopathological confirmed diagnosis of a locally advanced or metastatic solid tumor malignancy for which primary treatment is no longer effective or does not offer curative or life-prolonging potential per clinician judgment, with the understanding that DCVax-Direct is not intended as a treatment of last resort. Target indications for this study are listed in section 5.1 of this protocol.

4) Not eligible for complete resection due to tumor location, physician’s assessment or patient’s choice.

5) Must have completed at least one recent (<12 weeks prior to screening) treatment regimen in the metastatic or advanced setting in the disease currently under treatment to reduce tumor burden. If this criterion is not met, patients muct receive additional anti-tumor therapy as per section 6.3 of the protocol prior to the first DCVax-Direct injection.

6) Any steroid therapy >2 mg dexamethasone per day or equivalent dose should be stopped or have been tapered down 2 weeks prior to the leukapheresis.

7) At least one measurable tumor mass, i.e. a lesion that can accurately be measured by CT/MRI in at least one dimension with longest diameter = 1 cm, that is accessible for injection either with or without imaging (CT/ultrasound) guidance. The tumor mass for injection should not be invading a major vascular structure (e.g. carotid artery), and should not be in a location where post-treatment swelling could result in significant clinical adverse events (e.g. tumors impinging on the upper airway or affecting biliary tract drainage cannot be considered as sites for injection).

8) Adequate hematological, hepatic, and renal function, such as: Absolute lymphocyte count (ALC) >= 500/mm3; Absolute neutrophil count (ANC) >= 1000/mm3; Platelet count >= 100,000/mm3; Hemoglobin >= 9.0 g/dL; Total bilirubin <=1.5 mg/dL ; AST and ALT <= 2.5 × upper limit of normal (ULN), (AST/ALT < 5 × ULN if documented liver involvement); Creatinine <= 1.5x ULN. Deviations from these values are allowed if deemed ‘not clinically significant’ by the investigator.

9) Adequate blood coagulation parameters: INR <= 1.5 x ULN, PT/PTT <= 1.5 x ULN at screening.

10) Life expectation of >6 months (required to support intent of completing dosing through the fourth injection visit).

11) Sufficient doses of DCVax-Direct available for injection (as per Section 5.7). In Part 2, between 1 and 3 lesions will be injected with 2 million cells each, meaning that subjects with 3 lesions will require 3-fold more doses available for eligibility. a)1 injectable lesion: 6 injection visits with 2 million DC injected into one lesion; b) 2 injectable lesions: 6 injection visits with 2 million DC injected into each of 2 lesions [4 million DC per visit]; c) 3 or more injectable lesions: 6 injection visits with 2 million DC injected into each of 3 lesions [6 million DC per visit].
Exclusion Criteria: 1) Positive HIV-1, HIV-2, or HTLV-I/II tests.

2) History of current or prior (within the last two years) active clinically significant malignancy other than the tumor type for which DCVax-Direct treatment is considered , and except for primary tumor in the case of metastases and adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.

3) Presence of brain metastases, unless treated surgically and/or irradiated and clinically stable off steroids or on low dose (<= 2 mg qd) steroids for >= 14 days, or presence of leptomeningeal disease.

4) History of immunodeficiency or unresolved autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, scleroderma, polymyositis-dermatomyositis, juvenile onset insulin dependent diabetes, or vasculitis.

5) Requirement for ongoing immunosuppressants.

6) Prior active immunotherapy for cancer within the past 2 years, such as dendritic cell-based therapies, immunizations with inactivated tumor cells, or with adjuvanted tumor-derived proteins or peptides.

7) Ongoing medical need for continuous anti-coagulation or anti-platelet medication, such as warfarin, aspirin, ticlopidine, clopidogrel, dipyridamole (with the exception of low dose warfarin for line patency and prophylactic low molecular weight heparin or NSAIDS (see Section 9, Concomitant Medications for further clarification).

8) Known genetic cancer-susceptibility syndromes.

9) Acute infection: any active viral, bacterial, or fungal infection that requires specific therapy. Infection requiring therapy must have been resolved and/or therapy completed at least seven days prior to first immunization.

10) Active uncontrolled infection at screening. Examples are a sexually transmitted disease, herpes, scrofula, malaria, etc.

11) Ongoing fever >= 101.5oF/38.6oC at screening.

12) Unstable or severe intercurrent medical conditions such as unstable angina, uncontrolled arrhythmias, Crohn’s Disease, ulcerative colitis etc.

13) Females of child-bearing potential who are pregnant or lactating or who are not using adequate contraception (surgical, hormonal or double barrier, i.e. condom and diaphragm).

14) Allergy or anaphylaxis to any of the reagents used in this study.

15) Inability to obtain informed consent because of psychiatric or complicating medical problems.

16) Inability or unwillingness to return for required visits and follow-up exams.

17) Heavily pretreated (HP) subjects are not eligible for this study, unless treatments have occurred more than 1 year in the past. Examples of HP include the following: 3 or more courses of alkylating agents, anthracyclines, or platinum-based agents, either in isolation or in combination; 2 or more courses of mitomycin C; 25% or more of the bone marrow irradiated. Note: this specific exclusion does not apply if subject has adequate Complete Blood Count as defined in Inclusion Criterion 9.

18) Heavily myelosuppressive or myelotoxic chemotherapy within 4 weeks prior to the first injection. Note: this specific exclusion does not apply if subject has adequate Complete Blood Count as defined in Inclusion Criterion 9.