[Colored emphasis below is mine.]
A phase 2 study of intralesional PV-10 followed by radiotherapy for localized in transit or recurrent metastatic melanoma.
Author(s): Matthew C Foote, Bryan H Burmeister, Janine Thomas, Tavis Read, Bernard Mark Smithers; Princess Alexandra Hospital and University of Queensland, Brisbane, Australia; Princess Alexandra Hospital, Brisbane, Australia
Background: Intralesional rose bengal (IL PV-10) can elicit ablation of injected tumors and a T-cell mediated abscopal effect in untreated lesions. Phase 2 testing in patients with Stage III-IV melanoma yielded a 51% objective response rate (ORR) with 50% complete response (CR) when all disease was injected. Three patients who progressed received external beam radiotherapy (XRT) to their recurrent lesions with an impressive response without an increased radiation reaction. Methods: An open-label, single-arm phase 2 study was performed to assess efficacy and safety of IL PV-10 followed by XRT. Eligibility included recurrent localized dermal, subcutaneous, in-transit or metastatic malignant melanoma (stage IIIb / IIIc) suitable for intralesional therapy and XRT. Patients received a single course of PV-10 into lesions treatable within a localized radiotherapy field. If CR was not achieved patients received 30 Gy (6 fractions of 5 Gy twice weekly over 3 weeks) 3D conformal radiotherapy (photons or electrons) commencing 6-10 weeks after PV-10. Outcome assessments included ORR and clinical benefit (CR+PR+SD) of in-field target lesions by RECIST criteria, toxicity using CTCAE V3.0, and progression free survival (PFS). Results: There were 15 patients enrolled with 13 completing the radiotherapy component. Two patients had rapidly progressive distant disease following PV-10 injection. The mean age of patients was 69 years. With a median follow up duration of 19.3 months the overall response rate was 87% (CR 33%, PR 53%) with 93% clinical benefit on an intent-to-treat basis. The mean time to best response was 3.8 months, mean duration of complete response (PFS) 12.2 months, overall loco regional progression rate 80% and melanoma specific survival 65.5 months. Size of metastases ( < 10mm) predicted potential for lesion complete response. Treatments were well tolerated with no treatment associated grade 4 or 5 adverse events. Conclusions: The combination of IL PV-10 and radiotherapy resulted in lesion specific, normal tissue sparing, ablation of melanoma tumors with minimal local or systemic adverse effects. The study results justify expanded evaluation in a randomized trial.
Intralesional rose bengal for treatment of melanoma.
Author(s): Sanjiv S. Agarwala, Robert Hans Ingemar Andtbacka, Kristen N. Rice, Merrick I. Ross, Charles Raben Scoggins, Bernard Mark Smithers, Eric D. Whitman, Eric Andrew Wachter; St. Luke's Hospital and Health Network and Temple University, Bethlehem, PA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Medcl Onc Assoc of San Diego, San Diego, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Louisville, Louisville, KY; Princess Alexandra Hospital and University of Queensland, Brisbane, Australia; Atlantic Melanoma Ctr, Morristown, NJ; Provectus Biopharmaceuticals, Inc, Knoxville, TN
Background: Intralesional rose bengal (PV-10) is an investigational small molecule ablative immunotherapy that can elicit primary ablation of injected tumors and secondary T-cell activation. Phase 2 testing in Stage III-IV melanoma yielded a 51% objective response rate (ORR) with 50% complete response (CR) when all disease was injected. PV-10 is currently undergoing phase 3 testing as a single agent in patients with locally advanced cutaneous melanoma and phase 1b testing in combination with immune checkpoint inhibition for more advanced disease. Methods: Study PV-10-MM-31 (NCT02288897) is an international multicenter, open-label, randomized controlled trial of PV-10 versus investigator’s choice of chemotherapy (dacarbazine or temozolomide) or oncolytic viral therapy (talimogene laherparepvec). A total of 225 subjects with locally advanced cutaneous melanoma (Stage IIIB or Stage IIIC recurrent, satellite or in-transit melanoma) randomized 2:1 will be assessed for progression free survival (PFS) by RECIST 1.1 (using blinded Independent Review Committee assessment of study photography and radiology data). Comprehensive disease assessments, including review of photography and radiology data, are performed at 12 week intervals; clinical assessments of progression status are performed at 28-day intervals. Study PV-10-MM-1201 (NCT02557321) is an international multicenter, open-label, sequential phase study of PV-10 in combination with pembrolizumab. Stage IV metastatic melanoma patients with at least one injectable cutaneous or subcutaneous lesion who are candidates for pembrolizumab are eligible. In the current phase 1b portion of the study, up to 24 subjects will receive the combination of PV-10 and pembrolizumab (PV-10 + standard of care). In phase 2 an estimated 120 participants will be randomized 1:1 to receive either PV-10 and pembrolizumab or pembrolizumab alone. The primary endpoint for phase 1b is safety and tolerability with PFS a key secondary endpoint; PFS is the primary endpoint for phase 2. Clinical trial information: NCT02288897
Showing posts with label monotherapy. Show all posts
Showing posts with label monotherapy. Show all posts
May 18, 2016
June 7, 2014
"IL PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma"
Key opinion leaders in melanoma, like Europe's Dr. Axel Hauschild, M.D., Ph.D., see a role for intralesional agents in combination with other agents to treat metastatic melanoma. Hauschild, a member of OncoSec's Melanoma Advisory Board (OncoSec [OTCQB: ONCS] treats melanoma tumors using intratumoral electroporation of plasmid interleukin-12), led a poster highlights session for melanoma/skin cancers at ASCO 2014. In regard to all intralesional agents he noted (paraphrasing) they have no systemic toxicity, have high CR rates, and are good candidates for combinatorial use due to immune priming {underlined emphasis is mine}.
A very interesting conclusion from Moffitt's Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions ASCO poster was "IL PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma" (where IL means intralesional).
Moffitt's Dr. Vernon Sondak, M.D. will speak further about PV-10 at a symposium (see below) of the 4th European Post-Chicago Melanoma Meeting: Interdisciplinary Global Conference on News in Melanoma.
Moffitt's Dr. Vernon Sondak, M.D. will speak further about PV-10 at a symposium (see below) of the 4th European Post-Chicago Melanoma Meeting: Interdisciplinary Global Conference on News in Melanoma.
 |
| Click to enlarge |
Provectus has considered the role of PV-10 in combination therapies for some time.
Ex. #1-P (2011) The company began working with strategic advisory board member Dr. Craig Eagle, M.D. (Pfizer) as early as sometime in 2011 (I think) on joint Provectus-Pfizer patent application Combination of Local and Systemic Immunomodulative Therapies for Enhanced Treatment of Cancer. Although the patent was filed in March 2012, its priority data date was October 3, 2011, which coincidentally is the same date as AstraZeneca's MedImmune's MedImmune in-licenses cancer immunotherapy tremelimumab from Pfizer press release: "Under the terms of this agreement, MedImmune will assume global development rights to tremelimumab and Pfizer will retain the rights to use tremelimumab with specified types of combination therapies."
Ex. #2-P (2012) The company presented murine model data on PV-10 combination therapy -- PV-10 and systemic chemotherapy 5-fluorouracil -- applied to hepatocellular carcinoma and melanoma tumors at the October 2012 Society for Immunotherapy of Cancer annual meeting (see Provectus Presents Nonclinical Data on Antitumor Immune Response to PV-10 Immuno-Chemoablation): "Treatment of mice with systemic chemotherapy (i.e., 5-fluorouracil, "5-FU") had minimal effect on either tumor, while combination of intralesional PV-10 with systemic 5-FU elicited maximal response in uninjected tumors."
Ex. #1-P (2011) The company began working with strategic advisory board member Dr. Craig Eagle, M.D. (Pfizer) as early as sometime in 2011 (I think) on joint Provectus-Pfizer patent application Combination of Local and Systemic Immunomodulative Therapies for Enhanced Treatment of Cancer. Although the patent was filed in March 2012, its priority data date was October 3, 2011, which coincidentally is the same date as AstraZeneca's MedImmune's MedImmune in-licenses cancer immunotherapy tremelimumab from Pfizer press release: "Under the terms of this agreement, MedImmune will assume global development rights to tremelimumab and Pfizer will retain the rights to use tremelimumab with specified types of combination therapies."
Ex. #2-P (2012) The company presented murine model data on PV-10 combination therapy -- PV-10 and systemic chemotherapy 5-fluorouracil -- applied to hepatocellular carcinoma and melanoma tumors at the October 2012 Society for Immunotherapy of Cancer annual meeting (see Provectus Presents Nonclinical Data on Antitumor Immune Response to PV-10 Immuno-Chemoablation): "Treatment of mice with systemic chemotherapy (i.e., 5-fluorouracil, "5-FU") had minimal effect on either tumor, while combination of intralesional PV-10 with systemic 5-FU elicited maximal response in uninjected tumors."
 |
| Click to enlarge Generation of an antitumor response and immunity using a small molecule drug (PV-10) |
Ex. #3-P (2013) Provectus presented murine model data on PV-10 combination therapy -- PV-10 and a systemic immunotherapy anti-CTLA-4 antibody at the April 2013 American Association for Cancer Research ("AACR") annual meeting (see Provectus Presents Data on PV-10 Combination Therapy at American Association of Cancer Research Annual Meeting): "PV-10 and PV-10 plus 9H10 exhibited robust response in both treated and untreated tumors. The combination therapy was most effective in the low dose model, where advantages in tumor growth and survival benefit were most pronounced. Increased apparent toxicity of 9H10 at the higher dose levels highlighted the need for establishment of an optimal dose in future mechanism studies and clinical trials...This work shows that, as hypothesized, addition of the immunologic effects of an anti-CTLA-4 agent augments the benefits of PV-10. For visceral or other inaccessible disease, combination of PV-10 with CTLA-4 blockade offers important potential for synergy...PV-10's ability to reduce tumor burden and elicit tumor-specific immunologic stimulation make it a logical potential complement to anti-CTLA-4 agents, such as ipilimumab."
Ex. #4-P (2013) The company again discussed important contexts for PV-10 combination, such as "While more frequent dosing could potentially improve outcomes, for patients with extensive tumor burden inaccessible to PV-10 injections a combination therapy strategy may be attractive" (see June 2013's PV-10 Moves Forward): "In phase 2 and 3 clinical trials, Dr. Wachter pointed out, the higher doses of ipilimumab were associated with an increase in immune-related adverse effects, presumably mirroring the dose response seen in murine models with 9H10. Dr. Wachter concluded, “Examples of successful treatment of established B16 tumors in murine models are rare. These results demonstrate that when all existing tumor is accessible for injection, PV-10 is highly effective both in animal models and clinically in cancer patients. Given that tumor ablation with PV-10 induces tumor-specific immunity, the combination of PV-10 with CTLA-4 blockade has important potential for synergy.” Speaking further in an interview, he said, “I think the case has been made successfully for PV-10’s role as a potent stimulator of specific anti-tumor activity. This is evident in clinical data from Phase 1 and 2 testing, where regression of untreated bystander tumors correlated with ablation of tumors, and in these nonclinical mechanism studies. And, our recent murine studies show that this stimulation works robustly in combination with CTLA-4 blockade.”"
 |
| Click to enlarge Combination of PV-10 Immuno-chemoablation and Systemic Anti-CTLA-4 Antibody Therapy in Murine Models of Melanoma |
Ex. #5-P&M (2013-2014) Moffitt's Dr. Jeffrey Weber, in addition to his history of regulatory approval contributions to ipilimumab (Yervoy) and vemurafenib (Zelboraf) as monotherapies for metastatic melanoma, has successfully contributed to the approval of combination therapies (see Moffitt Cancer Center reports key role in FDA approval of Mekinist/Tafinlar for melanoma): "“This new combination therapy is a huge step in the right direction for the treatment of melanoma, and our researchers played a large role in bringing this treatment option to patients,” Jeffrey S. Weber, MD, PhD, director of Moffitt’s Melanoma Research Center of Excellence, Tampa, Fla., said in a press release...“A clinical trial in which Moffitt was the major contributor showed a 76% success rate for patients treated with the Mekinist and Tafinlar combination,” Weber said. “We also found this therapy reduced the incidence and severity of some of the toxic effects patients experienced when the drugs were used alone.”"
In the same Provectus-sponsored white paper referenced in Ex. #4-P (2013) above, Eric is further quoted: "Further studies designed to confirm the apparent synergy are underway, including one with only the low 9H10 dose/ PV-10 combination. A phase 1/2 anti-CTLA-4 dose escalation trial with PV-10 is warranted, Dr. Wachter said. Similarly, models for kinase inhibitors and an analogue for vemurafenib are being sought. Vemurafenib, like PV-10, rapidly reduces tumor burden. PV-10 murine research demonstrated unambiguously, Dr. Wachter noted, that tumor burden is a critical variable in predicting response to a combination therapy. It has been suggested that earlier research into therapeutic melanoma vaccines faltered because tumor burden grew beyond the immune system’s capacity for control before the vaccine could develop its full effect. “We think that the combination of PV-10 with something like a kinase-inhibitor has the potential to dial back or reduce tumor burden even better than an anti-CTLA-4 agent while the systemic PV-10 immunologic effect is developing. The kinase inhibitor would do the early work against visceral disease until PV-10 can catch up and take the baton across the finish line.” While the PD-1 And PD-L1 drugs will be interesting candidates for combinations, because none are approved, testing is currently impractical."
Recall Eric's comments regarding Moffitt from the May 23rd conference call presented in my post "Why did it take four years...to arrive at this point?": "We began a dialogue with researchers from Moffitt Cancer Center early in 2011." This dialogue resulted in work conducted by Moffitt that was presented at:
In the same Provectus-sponsored white paper referenced in Ex. #4-P (2013) above, Eric is further quoted: "Further studies designed to confirm the apparent synergy are underway, including one with only the low 9H10 dose/ PV-10 combination. A phase 1/2 anti-CTLA-4 dose escalation trial with PV-10 is warranted, Dr. Wachter said. Similarly, models for kinase inhibitors and an analogue for vemurafenib are being sought. Vemurafenib, like PV-10, rapidly reduces tumor burden. PV-10 murine research demonstrated unambiguously, Dr. Wachter noted, that tumor burden is a critical variable in predicting response to a combination therapy. It has been suggested that earlier research into therapeutic melanoma vaccines faltered because tumor burden grew beyond the immune system’s capacity for control before the vaccine could develop its full effect. “We think that the combination of PV-10 with something like a kinase-inhibitor has the potential to dial back or reduce tumor burden even better than an anti-CTLA-4 agent while the systemic PV-10 immunologic effect is developing. The kinase inhibitor would do the early work against visceral disease until PV-10 can catch up and take the baton across the finish line.” While the PD-1 And PD-L1 drugs will be interesting candidates for combinations, because none are approved, testing is currently impractical."
Recall Eric's comments regarding Moffitt from the May 23rd conference call presented in my post "Why did it take four years...to arrive at this point?": "We began a dialogue with researchers from Moffitt Cancer Center early in 2011." This dialogue resulted in work conducted by Moffitt that was presented at:
- The March 2012 annual meeting of the Society of Surgical Oncology (see Intralesional Injection of Melanoma with Rose Bengal Induces Regression of Untreated Synchronous Melanoma in a Murine Model),
- The April 2013 AACR annual meeting (see Intralesional Injection with PV-10 Induces a Systemic Anti-tumor Immune Response in Murine Models of Breast Cancer and Melanoma),
- The April 2014 AACR annual meeting (see Induction of anti-melanoma immunity after intralesional ablative therapy [poster not yet released by Moffitt]), and
- The April 2014 American Society of Clinical Oncology ("ASCO") (see Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions).
- Co-author: Jeffrey S. Weber
- Poster abstract: "Further studies are ongoing to determine the mechanism by which PV-10 increases tumor-specific T cell responses as well as to establish the interaction of intralesional PV-10 with combination checkpoint protein inhibition" {underlined emphasis is mine}
- Poster conclusion: "IL PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma."
The focus of Moffitt's ASCO poster was the center's work with PV-10 in its human feasibility study. As such, I presume Moffitt/Weber's combination exploration and work (presumably murine model studies) will be presented at a later date.
Provectus: "“We think that the combination of PV-10 with something like a kinase-inhibitor has the potential to dial back or reduce tumor burden even better than an anti-CTLA-4 agent while the systemic PV-10 immunologic effect is developing. The kinase inhibitor would do the early work against visceral disease until PV-10 can catch up and take the baton across the finish line.”"
"Whenever T cells and B cells are activated, some become "memory" cells. The next time that an individual encounters that same antigen, the immune system is primed to destroy it quickly. This is active immunity because the body's immune system prepares itself for future challenges" (Source material: Understanding Cancer Series: The Immune System, National Cancer Institute).
In elucidating PV-10's mechanism of immune response (the second of the drug's two-step mechanism of action, the first step being ablation) Provectus noted Moffitt researchers, in their AACR 2014 poster (human feasibility study), showed "...significant decreases in melanoma cells in injected tumors and uninjected bystander tumors 7-14 days after PV-10 injection as evidenced by pathologic evaluation confirmed with immunohistochemical staining of biopsy specimens for melA (a marker of melanoma)... were accompanied by increased populations of CD3+, CD4+ and CD8+ T cells along with NKT cells in peripheral blood." Moffitt concluded in their ASCO 2014 poster that "IL PV-10 can enhance tumor-specific reactivity in circulating T-cells."
It seems to me chemoablation via PV-10 ablation causes antigenization, antigenization causes immunization. PV-10 causes antigenization. Antigenization causes immunization. Antigenization is the expression of antigens, in a tumor into which PV-10 has been injected, in context. Immunization is "the process by which...[the] immune system becomes fortified against an agent." PV-10 facilitates the relationship between antigenization and immunization.
Provectus: "“We think that the combination of PV-10 with something like a kinase-inhibitor has the potential to dial back or reduce tumor burden even better than an anti-CTLA-4 agent while the systemic PV-10 immunologic effect is developing. The kinase inhibitor would do the early work against visceral disease until PV-10 can catch up and take the baton across the finish line.”"
"Whenever T cells and B cells are activated, some become "memory" cells. The next time that an individual encounters that same antigen, the immune system is primed to destroy it quickly. This is active immunity because the body's immune system prepares itself for future challenges" (Source material: Understanding Cancer Series: The Immune System, National Cancer Institute).
In elucidating PV-10's mechanism of immune response (the second of the drug's two-step mechanism of action, the first step being ablation) Provectus noted Moffitt researchers, in their AACR 2014 poster (human feasibility study), showed "...significant decreases in melanoma cells in injected tumors and uninjected bystander tumors 7-14 days after PV-10 injection as evidenced by pathologic evaluation confirmed with immunohistochemical staining of biopsy specimens for melA (a marker of melanoma)... were accompanied by increased populations of CD3+, CD4+ and CD8+ T cells along with NKT cells in peripheral blood." Moffitt concluded in their ASCO 2014 poster that "IL PV-10 can enhance tumor-specific reactivity in circulating T-cells."
It seems to me chemoablation via PV-10 ablation causes antigenization, antigenization causes immunization. PV-10 causes antigenization. Antigenization causes immunization. Antigenization is the expression of antigens, in a tumor into which PV-10 has been injected, in context. Immunization is "the process by which...[the] immune system becomes fortified against an agent." PV-10 facilitates the relationship between antigenization and immunization.
Subscribe to:
Posts (Atom)